Preface

In recent years, there has been a great deal of interest amongst nutritionists and other health professionals to include other biologically active compounds from plant and animal sources in our diets. Recent research has shown some of these compounds to have human health benefits. They are referred to as phytonutrients, nutraceuticals, functional ingredients, and beneficial bioactive compounds. Several compounds having different chemical properties, biological activities, and mechanisms of action are included in this group of biologically active compounds. Although these compounds are classified and grouped based on several factors, the most common category relates to their solubility either in water, such as polyphenols, or in lipids, such as carotenoids. This book addresses various aspects of carotenoids, such as alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin, and their role in human nutrition. It provides recent information on their sources, physical, chemical, and biochemical properties, isolation and characterization procedures, mechanisms of action, and basic and clinical studies currently being undertaken to gain information on their role in health and disease management.

In recognition of the importance of carotenoids in human health, this book contains chapters authored by well-known international researchers that present current information for researchers, consumers, nutritionists and other health care professionals, and government regulatory agencies. The book is organized into four sections.

Section 1, "Overview of the Role of Carotenoid in Human Health", includes one chapter. Chapter 1, "Introductory Chapter: Dietary Carotenoids – Sources, Properties, and Role in Human Health" by Akkinapally Venketeshwer Rao and Leticia Rao, provides an overview of carotenoids, their sources, properties, and their role in the prevention and management of human diseases. It concludes by identifying the need for future research for a better understanding of the role of carotenoids in human health.

Section 2, "Dietary Carotenoids in Health Management", includes three chapters. Chapter 2, "Recent Advancement in Therapeutic Activity of Carotenoids" by Anju Singh and Kamya Omer, provides a detailed description of the therapeutic activity of a few important carotenoids. Chapter 3, "Significance of Carotenoids in Traditional Medicines in the Republic of Suriname (South America)" by Dennis R.A. Mans, describes what traditional medicines are and how carotenoids influence their effects. Chapter 4, "A Perspective on Carotenoids: Z/E-Isomerization, Extraction by Deep Eutectic Solvents and Applications" by Jiahao Yu and Catherine M.G.C. Renard, provides current information about carotenoids and their role in health management. These three chapters together provide a clear understanding of the role of dietary carotenoids in the prevention and management of chronic diseases.

Section 3, "Dietary Sources of Carotenoids and their Bioavailability", includes two chapters. Chapter 5, "Carotenoids: Sources, Bioavailability and Their Role in Human Nutrition" by Indu Sharma, Neeraj Khare, and Archana Rai, examines

the sources of carotenoids and their bioavailability and role in human nutrition. Chapter 6, "Bioactive Properties of the Pigment Astaxanthin from *Haematococcus pluvialis* in Human Health", by Janeth Galarza, Bryan Pillacela, and Bertha Olivia Arredondo-Vega, deals specifically with an important carotenoid called astaxanthin.

Section 4, "Carotenoid in Disease Management", includes the final chapter. Chapter 7, "Role of Carotenoids in Parkinson's Diseases" by Fengjuan Jiao, highlights that the role of carotenoids in common human diseases such as cancer, cardiovascular diseases, ocular diseases, and diabetes has been studied extensively. However, the role of carotenoids in other human chronic diseases, such as Parkinson's disease, is just beginning to be studied.

Overall, this book provides important information about various carotenoids, their dietary sources, mechanisms of action, and their role in the management and prevention of chronic human diseases. It is a useful reference for consumers, researchers, health professionals, and regulatory personnel.

#### **Akkinapally Venketeshwer Rao**

Faculty of Medicine, Department of Nutritional Sciences, University of Toronto, Canada

#### **Leticia Rao**

Faculty of Medicine, Department of Medicine, University of Toronto, Canada

Section 1

## Overview of the Role of Carotenoid in Human Health

#### **Chapter 1**

## Introductory Chapter: Dietary Carotenoids – Sources, Properties, and Role in Human Health

*Akkinapally Venketeshwer Rao and Leticia Rao*

#### **1. Introduction**

Global dietary guidelines recommend increased consumption of plant-based foods as a good source of essential nutrients, such as vitamins and minerals. However, recent research has shown that plants also contain a wide variety of biologically active compounds other than the essential nutrients that may play an important role in human nutrition and health. Over the past few decades, extensive research has been directed at identifying these biologically active compounds, their chemical properties, and biological activities and mechanisms of action. It is now recognized that consumption of these compounds is an important complimentary approach in the prevention, treatment, and management of several of human diseases. Although, technically they are not recognized as nutrients but are referred to as "phytonutrients," "nutraceuticals," "functional ingredients," and "beneficial bioactive compounds" [1]. The scope of these compounds has now expanded beyond foods to include therapeutics, pharmaceuticals, and cosmeceuticals. Unlike essential nutrients, there are no recommended levels of daily intake for these compounds as of now. Several thousand phytonutrients have been identified as being present in plants. Although not all of them have been studied in detail, two classes of the phytonutrients that have been studied extensively include the water-soluble and the fat-soluble carotenoids [2]. The focus of this book is in the area of carotenoids and their role in human nutrition and health.

Carotenoids are organic pigments produced mainly by plants. However, some algae, bacteria, and fish have also been known to contain carotenoids. They are responsible for a full spectrum of colors all the way from yellow to red. The recent recommendation by health professionals to consume multicolored foods reflects the importance of carotenoids as an important part of a healthy diet [3]. Over 1000 carotenoids have so far been identified and classified into xanthophylls containing oxygen in their molecule and carotenes contain no oxygen. Carotenoids, amongst which β-carotene is an important and well-known carotene. Other important carotenes include α-carotene, lycopene, β-cryptoxanthin, and lutein. They contain eight isoprene molecules and 40 carbon atoms. One of the characteristic features of carotenes is the presence of multiple, ranging from 9 to 11, conjugated double bonds [2, 4].

The typical chemical structure of β-carotene is shown in **Figure 1**.

Humans cannot synthesize carotenoids in their bodies and must get them from their diet. Many studies have shown that low intake of carotenoids, low concentration

**Figure 1.** *Basic structure of a β-carotene showing 9 conjugated double bonds.*

of serum carotenoids, and low accumulation of carotenoids in various organs, such as skin and eyes, are risk factors for developing the abovementioned disorders. Taking carotenoid-rich foods and supplements has been shown to reduce these risks [5].

The antioxidant property of carotenoids is associated with the presence of these conjugated double bonds. Oxidative damage is closely associated with inflammatory damage of tissues, and in turn, with initiation and progression of several human chronic diseases [6–9]. To understand the role of carotenoids in human health, several *in vitro*, animal, preclinical, and clinical studies have been undertaken over


#### **Table 1.**

*Examples of some food sources of major carotenoids in the North American Diet.*

the past decade. Prevention of cardiovascular diseases was the focus of most of the initial studies directed at carotenoids [2]. This was later followed by studies that were directed at understanding their role in the initiation, management, and possible treatment of cancer, age-related macular degeneration, diabetes, and male infertility. More recently there is great interest in studying the role of carotenoids in immune deficiency-related diseases and neurodegenerative disorders. Diseases related to bone, such as osteoporosis are also areas of recent research.

Common carotenoids, their food sources, and amounts are shown in **Table 1**. The amounts shown in the table an approximation and vary depending on several factors.

#### **2. Challenges and future research**

Since the discovery of β-carotene in carrot juice almost two centuries ago, several thousand more carotenoids have now been identified. Over the past couple of decades, a great deal of advancement has been made in terms of our understanding the role of carotenoids in human health. Studies have produced information in terms of the chemical and biological properties of carotenoids, their dietary sources, and mechanisms of action. Martini et al. [10] in 2022 provided insight into the future directions in research related to carotenoids. Similarly, Melendez-Martinez et al. [11] and Rocha et al. [12] also pointed out to the need for future research on carotenoids and human health.

In recent years, a few of the carotenoids have been subjected to basic, preclinical, and clinical investigations to understand their role in human nutrition and health. More new knowledge about carotenoids is now being generated relating to their chemistry, dietary and supplemental sources, biological properties, mechanisms of action, and their role in human health. However, there is still a need for clear understanding about the results, particularly from limited number of interventional clinical studies.

Recognizing the need for more recent information, this book is being published to present the readers up to date knowledge on carotenoids, including techniques of isolation; characterization of their chemical, physical, and biochemical properties; sources; mechanisms of action; and basic *in vitro*, animal, and observational. Preclinical and clinical studies are currently being undertaken to gain information


#### **Table 2.**

*Some examples of the biological properties and disease prevention of carotenoids.*

relating to their role in human health and diseases. This book will be of interest not only to the scientific community undertaking research but also to the consumers who are concerned more and more about their diet and health. It will also be of interest to government regulating agencies in developing regulatory guidelines for the safety of carotenoids and to validate their claimed benefits in human health, disease prevention and management, and even in the possibility of treatment of the diseases in the future.

Some of the biological mechanisms and disease prevention of carotenoids are shown in **Table 2**.

### **Author details**

Akkinapally Venketeshwer Rao1 \* and Leticia Rao2

1 Faculty of Medicine, Department of Nutritional Sciences, University of Toronto, Canada

2 Faculty of Medicine, Department of Medicine, University of Toronto, Canada

\*Address all correspondence to: venket.rao18@gmail.com

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Introductory Chapter: Dietary Carotenoids – Sources, Properties, and Role in Human Health DOI: http://dx.doi.org/10.5772/intechopen.114063*

#### **References**

[1] Rao V. Phytochemicals. A global Perspective of Their Role in Nutrition and Health. London, UK: IntechOpen; 2020

[2] Bakan E et al. Carotenoids in foods and their effects on human health. Akademik Gıda. 2014;**12**:61-68

[3] Crupi P et al. Overview of the potential beneficial effects of carotenoids on consumer health and well being. Antioxidants (Basel). 2023;**12**:1069

[4] Dale A. Carotenoids in health and disease: Recent scientific evaluations, research recommendations, and the consumer. The Journal of Nutrition. 2004;**134**:221S-224S

[5] Rodrguez-Concepcion M et al. A global perspective on carotenoids: Metabolism, biotechnology, and benefits for nutrition and health. Progress in Lipid Research. 2018;**70**:62-93

[6] Rao AV, Rao LG. Carotenoids and human health. Pharmacological Research. 2007;**65**:207-216

[7] Rao V, Rao LG. Phytochemicals: Isolation, Characterisation, and Role in Human Health. London, UK: IntechOpen; 2015

[8] Bhatt T, Patel K. Carotenoids: Potent to prevent diseases review. Natural Products and Bioprospecting. 2020;**10**:109-117

[9] Rao AV, Agarwal S. Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: A review. Nutrition Research. 1999;**19**:305-323

[10] Martini D et al. What is the current direction of the research on carotenoids and human health? An overview of registered clinical trials. Nutrients. 2022;**14**:1191

[11] Meléndez-Martínez AJ et al. A comprehensive review on carotenoids in foods and feeds: Status quo, applications, patents, and research needs. Critical Reviews in Food Science and Nutrition. 2022;**62**:1999-2049

[12] Rocha H, Coelho M, Gomes AM, Pintado ME. Carotenoids diet: Digestion, gut microbiota modulation, and inflammatory diseases. Nutrients. 2023;**15**:2265

Section 2

## Dietary Carotenoids in Health Management

#### **Chapter 2**

### Recent Advancement in Therapeutic Activity of Carotenoids

*Anju Singh and Kamya Omer*

#### **Abstract**

Carotenoids are a class of organic pigments that are widely distributed in nature and are responsible for the bright colours of many fruits and vegetables. Carotenoids are found in many plant-based foods such as carrots, sweet potatoes, spinach, kale, and tomatoes. Some of the most well-known carotenoids include beta-carotene, lutein, zeaxanthin, and lycopene. Lutein and zeaxanthin are concentrated in the eyes and have been shown to protect against age-related macular degeneration, a leading cause of blindness in the elderly. Lycopene is found in high concentrations in tomatoes and has been associated with a reduced risk of prostate cancer. Recent research has focused on the potential therapeutic applications of carotenoids for the treatment of various diseases. For example, astaxanthin, a carotenoid found in salmon and other seafood, has been shown to have anti-inflammatory and antioxidant properties and may be useful in the treatment of conditions such as arthritis and cardiovascular disease. Similarly, lycopene has been investigated for its potential to prevent or treat certain types of cancer, including prostate, lung, and breast cancer. In addition to their potential health benefits, carotenoids are also being studied for their role in the prevention of cognitive decline and ageing-related diseases. Ongoing research is exploring their potential therapeutic applications for the treatment of various conditions, including cancer, cardiovascular disease, and cognitive decline. On completion of the chapter you shall be able to explain: (1) the sources and classification of carotenoids, (2) the bioactive compounds used to in various treatments and (3) novel discoveries related to carotenoids.

**Keywords:** carotenoids, therapeutic activity, bioactive compounds, carotene, xanthophylls, disease prevention and treatment

#### **1. Introduction**

The vibrant colours found in fruits and vegetables are due to carotenoids, a type of pigment. Carotenoids are dietary tetraterpenoid (C40 containing eight isoprenoid residues) chemicals that play an important function in cell defence [1, 2].

These naturally occurring, lipid-soluble, highly unsaturated red, yellow, or orange pigments are found in plants, fungus, bacteria, and algae, and the quantity of carotenoids determines how intense the colour is. As naturally occurring elements of fruits and vegetables, these have been widely distributed. Carotenoids are responsible for the coloration of many flowers, birds, and marine animals [3]. Carotenoids'

therapeutic activities and actions are determined by their molecular structure, that defines their physical and chemical qualities.

It's interesting to know that there are approximately 600 known carotenoids, and some experts think the actual number may be closer to 750. However, only 100 of these carotenoids are commonly found in the food we eat. The top five carotenoids, such as α-carotene, β-carotene, lycopene, β-cryptoxanthin, lutein, and zeaxanthin, make up a significant 95% of our diet. These carotenoids have been extensively researched over the years, as they play crucial roles in photobiology, photochemistry, and photomedicine [4].

Carotenoids are frequently referred to as provitamin A because this vitamin is a by-product of carotenoid metabolism. They are gaining popularity due to their supposed antioxidant effects. Decades of research on carotenoids have improved our understanding of their role as important players in the prevention of ageing-related diseases such as cancer, cardiovascular disease, cataracts, and age-related macular degeneration [5]. Carotenoids' numerous health advantages have motivated their incorporation in foods and beverages as nutraceuticals and nutritional supplements.

Carotenoids research is progressing in three major areas:


They can be present in a broad range of foods made from plants and have been linked to a lower risk for long-term diseases. Global demand for carotenoids is expected to rise from a value of US\$1.5 billion in 2014 to a total of US\$1.8 billion in 2019. Carotenoids from natural sources are used to make some of the commercially available carotenoids. Synthetic carotenoids have some advantages over natural carotenoids. First, synthesised carotenoids are particularly constructed to minimise oxidation or isomerization, making them more stable. Synthetic carotenoids are created in colloidal suspension, emulsification, and dispersion colloids to make carotenoid application in food easier. They are commonly sold on the market as soluble in water and stable emulsions.

Despite these benefits, chemically produced carotenoids are known to have significant levels of toxicity, carcinogenicity, and teratogenicity. As a result, customers who care about their health have a lot of reservations about them. As a result, carotenoids derived from natural resources are highly sought after by today's customers.

#### **2. Chemistry of carotenoids**

Carotenoids are a class of pigments found mostly in plants that are responsible for the vibrant yellow, orange, and red colours found in vegetables and fruits [6]. All have antioxidant action, and some are vitamin A precursors. Furthermore, carotenoids play a function in interaction between cells, immune system activation, and illness prevention, promoting human health [7].

Carotenoids are made up of eight repeating units of isoprene with cyclic or linear structures at both ends, resulting in numerous cis and trans isomers, with the latter type being more prevalent in nature [8].

#### **3. Classification of carotenoids**

Carotenoids are categorised based on their chemical structure or their usefulness.


Primary carotenoids are photosynthetic pigments that play an important role in photosynthesis. Carotenes with orange to red wavelengths are responsible for transporting light energy from chlorophyll-absorbed sunlight. They are also known to operate as plant antioxidants by collecting energy from singlet oxygen generated during photosynthesis [9]. Xanthophyll molecules, on the other hand, are plentiful in plant leaves but do not play a direct role in photosynthesis. Xanthophylls absorb a wavelength of sunlight that chlorophyll does not. Plants use them as secondary carotenoids or as supplementary pigments.

#### **3.1 Xanthophylls**

Xanthophylls are soluble in both polar (e.g., alcohols) and organic (e.g., ether and hexane) solvents.

Xanthophylls are made up of hydrogen, carbon, and one or more functional groups including oxygen. They are oxygenated carotenoid derivatives that generate alcohols, aldehydes, ketones, and acids. Fucoxanthin, lutein, and violaxanthin are examples of xanthophylls.

Xanthophylls are naturally present in the tissues of green plants, but they only appear as fatty acid esters in fruits and flowers.

They are, however, slightly soluble in oils at ambient temperature as well as nonpolar organic solvents such as chloroform and acetone.

#### **3.2 Carotenes**

Carotenes are pure hydrocarbons. Plants and numerous microorganisms synthesise carotenoids in nature [10]. Animals can metabolise them in a specific way, but they cannot synthesise them. Carotenoids degrade slowly in storage, with losses varying depending on the matrix and storage circumstances [11].

Plant tissues, or plastids, such as chromoplasts (coloured plastids), amyloplasts (starch storage plastids), and elaioplasts (lipid storage plastids), are where carotenoids are stored. Carotenoids are found in the chromoplasts of fruits, flowers, and roots, whereas they are found in the amyloplasts and elaioplasts of grains and oilseeds, respectively.

Plants' carotenoids are typically lipid-based and insoluble in water; they are found in the chloroplast cells. Due to their water insolubility, they do not leach away when the veggies are prepped and cooked. They also do not significantly alter colour with heat or pH, especially if the chloroplast cells are still largely intact.

Carotenoids are terpenoids that are synthesised from the fundamental C5-terpenoid precursor, isopentyl diphosphate. Geranyl-geranyl diphosphate is formed from this chemical [11]. Its dimerisation produces phytoene, which is then dehydrogenated stepwise via phytofluene, zeta-carotene, and neyrosporene to produce lycopene. The additional naturally occurring carotenoids are produced through further oxidation, dehydrogenation, and cyclization processes.

Technology has advanced to the point that it is now possible to synthesise carotenoids with well-controlled, reproducible hues, without quality variations, and in a volume that can be scheduled to suit the needs of the food industry [12].

#### **4. Natural occurrence of carotenoids**

Only 40 of the more than 700 known carotenoids are present in the diet of humans, with α-carotene, β-carotene, lycopene, β-cryptoxanthin, lutein, and zeaxanthin being the most prevalent ones (**Table 1**) [44].

In paprika and pepper, the xanthophylls violaxanthin (yellow), capsanthin, and capsorubin (orange to red) are usually present. Neoxanthin, which has a yellow tint, is a naturally occurring component found in vegetable leaves. Saffron's yellow hue can be attributed to crocin [45].

Some carotenoids can only be found in algae or seafood. Due to its natural occurrence in krill and the microalga hematococcus pulvialis, which are eaten by small crustaceans like prawn and crawfish, fish like salmon and birds like flamingos, astaxanthin gives prawn, salmon and flamingo feathers their pink-red hue.

Based on the levels of carotenoid in the foods, Britton and Khachik [46] developed a ranking of vegetables and fruits. They divided foods into the following categories:


Many factors influence the composition and number of carotenoids in food, including:


#### *Recent Advancement in Therapeutic Activity of Carotenoids DOI: http://dx.doi.org/10.5772/intechopen.112580*


#### **Table 1.**

*Carotenoids with their sources and bioactivity/pharmacological activity [13–15].*

#### **5. Dietary carotenoids in foods**

The main dietary carotenoids include the hydrocarbons beta-carotene, alpha-carotene, and lycopene, as well as the xanthophylls, or oxygen-containing carotenoids, cryptoxanthin, lutein, and zeaxanthin [47].

#### **5.1 Beta-carotene**

The most extensively researched carotenoid is beta-carotene, which is also a prominent carotenoid in our diet as well as in our blood and tissues. It is a bright red-orange pigment found in many plants and fruits. Green leafy vegetables, as well as orange and yellow fruits and vegetables [48], such as carrots, sweet potatoes, mangoes, pumpkin, kale, spinach, apricots, pepper, cantaloupe, lettuce, and tomato paste, are high in betacarotene. Because carotenes are fat soluble, eating them with fat improves absorption.

#### **5.2 Lycopene**

Lycopene is a brilliant red carotene pigment and phytochemical that plants and microorganisms produce; absorbs light during photosynthesis and protect them from photosensitization. Despite being a carotene chemically, lycopene has no vitamin A action [47].

Heating tomatoes in oil was observed to be related with an increase in lycopene absorption when compared to unprocessed tomato juice absorption, similar to the effect on beta-carotene bioavailability [49]. Furthermore, lycopene bioavailability was higher with a single dose of tomato paste than with an identical lycopene dose of fresh tomatoes.

#### **5.3 Lutein and zeaxanthin**

Dark green leafy foods like spinach and kale contain lutein, a significant carotenoid [50]. Lutein is chemically distinct from other carotenoids. One of the most frequent carotenoid alcohols discovered in nature is zeaxanthin. Lutein and zeaxanthin are similar in terms of food sources, human metabolism, and tissue storage. Although the levels are modest in eggs, recent research indicates that both zeaxanthin and lutein from this kind of food are highly accessible.

#### **6. Therapeutic activity of carotenoids**

See **Figure 1** [53, 54].

#### **6.1 Anti-ageing activity**

One of the main signs of ageing is considered to be the onset and development of atherosclerosis. One of the causes of atherosclerosis is the inflammation-induced generation of reactive oxygen species (ROS) by atherosclerotic plaque.

Age-related blood vessel damage and endothelial dysfunction are caused by the degree of ROS present, which promotes the development of atherosclerosis. Additionally, a decrease in nitric oxide (NO) in the vascular tissue contributes to atherosclerosis and the ageing process brought on by ROS. However, the bioavailability or concentration of NO is often high in normal vascular tissue. Through a number of

#### **Figure 1.** *Carotenoids to prevent disease [24, 51, 52].*

processes, including the preservation of normal blood flow in organs via flow/shear stress-mediated vasodilation, NO produced in the endothelium inhibits atherosclerotic vascular ageing. One of the primary ways for preventing anti-vascular ageing is maintained vasodilation, which mediates blood flow in organs.

Carotenoids such as lutein, lycopene, and others prevent vascular ageing by anti-oxidant action, which increases the bioavailability of NO in the vascular system. Tomato extracts containing -carotene and lycopene consistently lower blood pressure while increasing NO levels in the plasma [55].

Many other studies have demonstrated lycopene's actions as an inhibitor of inflammation and ROS, as well as in the amelioration of inflammatory-mediated atherosclerotic processes. Specifically, lutein and lycopene, as well as other carotenoids, impede this process by lowering the level of ROS in biological systems. The anti-oxidant activity of lutein was demonstrated in vascular smooth muscle cells.

#### **6.2 Osteo-protective activity**

Carotenoids like β-cryptoxanthin have the ability to regulate the health of bone and inhibit osteoporosis. β-Cryptoxanthin intake increases calcium content and alkaline phosphatase activity in cortical bone and metaphyseal tissues in vitro, leading to a stimulatory effect on bone resorption, which eventually minimises the risk of osteoporosis. The intake of reinforce juice which has higher β-cryptoxanthin than a usual juice, displayed a preventive action on loss of bone. Long term intake of juice containing β-cryptoxanthin results to activation of bone formation and preventive action on reabsorption of bone in humans, which is favourable among menopausal women.

#### **6.3 Antioxidant activity**

One of the most effective singlet oxygen scavengers in nature has been shown to be carotenoids, which have a quick quenching rate (1010 M1 s1). They can effectively neutralise ROS and other free radicals to provide oxidation protection for both photosynthetic and non-photosynthetic species. Many epidemiological and clinical research have been conducted to determine whether carotenoids have the ability to protect various ROS-mediated illnesses such as cancer, inflammation, retinal degeneration, and neurodegeneration [56].

Carotenoids have antioxidant properties, but they can also activate endogenous antioxidant enzymatic activity and reduce DNA damage to shield cells from the oxidative stress brought on by specific stimuli. Crocetin, a pharmacologically active metabolite of *Crocus sativus* L., shows cardioprotective benefits by enhancing superoxide dismutase (SOD) and glutathione peroxidase activity in ventricular hypertrophy. It has also been demonstrated that crocin, another *Crocus sativus* L. component, increases SOD activity to stop PC-12 cells from dying when they are denied glucose or serum.

Recent research has shown that marine carotenoids like astaxanthin and fucoxanthin exhibit antioxidant characteristics as well by energising the antioxidant network, which includes SOD and catalase [30]. In addition, beta-cryptoxanthin shields human cells from H2O2-induced harm by promoting DNA oxidation-related damage repair in addition to its antioxidant activities. At low doses, lycopene and -carotene also protect against DNA damage. However, at greater concentrations, the opposite effects have been observed in cells undergoing oxidative damage [14].

#### **6.4 Effect of carotenoids on neurodegenerative disease**

Neurodegenerative diseases are neuronal disorders characterised by increasing neuronal loss and protein aggregation [34]. The most common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although the causes of these neurodegenerative diseases differ, they share certain traits that may be intimately associated to disease start and progression through inducing neuronal cell death.

One common trait is oxidative stress caused by increased ROS production throughout disease progression. ROS are reactive compounds containing oxygen that can target and damage live cell macromolecules such as lipids, DNA, and proteins. Various cellular processes, such as mitochondrial insults and the production of redox metals that interact with oxygen, raise the amount of ROS in the neuronal cells of patients with neurodegenerative disorders, which leads to neuronal cell death [57].

In a case of Alzheimer's disease, the most studied neurodegenerative disease, multiple studies have found reduced quantities of carotenoids including beta-carotene, lutein, and vitamin A in the blood plasma of Alzheimer's patients. A recent casecontrol study found that the concentration of six key carotenoids in serum (alphacarotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, and zeaxanthin) was considerably lower in individuals with Alzheimer's disease [58].

Carotenoid consumption reduced the risk of Alzheimer's disease and the rate of cognitive deterioration. Antioxidant supplementation, like astaxanthin and a vitamin complex containing alpha-tocopherol, ascorbic acid, and beta-carotene, lowered Aβ levels in red blood cells and ROS production in AD patients' cells, respectively [59].

Carotenoids' diverse modes of action are expected to occur concurrently in neurodegenerative disease states. Lycopene, for example, reduced A-induced mitochondrial dysfunction, inflammatory cytokine mediators, and caspase-3 activity all at the same time. A-induced damage was reduced in a cultured cell model by astaxanthin administration by many pathways, including downregulation of apoptotic factors, suppression of inflammatory cytokine mediating activity, and concomitant reduction of ROS.

#### **6.5 Anticancer activity**

A carotenoid can help prevent cancer through a variety of processes. A carotenoid, as a provitamin A, would influence cellular differentiation and proliferation. Furthermore, the antioxidant action may protect cellular DNA and other components from free radical damage Immunomodulatory effects may improve immune surveillance during carcinogenesis and improved cell-cell communication may limit the clonal proliferation of started cells.

Carotenoids are known to stop the cell cycle in the majority of cases, which is related with decreased expression of cyclin D1, cyclin D2, CDK4 and CDK6. As a result, it up regulates GADD45, which blocks cell entrance into S phase [60].

Furthermore, chemicals derived from saffron such as crocin and crocetin demonstrated anti-metastasis properties such as anti-migration, anti-invasive, and anti-non-adhesive effects when used together on the 4T1 cell line in breast cancer [55, 61]. Carotenoids such as beta-cryptoxanthin and lycopene have been discovered to block the NF-B signalling pathway, which is effective for lung and prostate cancer. Beta-carotene has been proven to have anti-angiogenic action, which means it helps to prevent the formation of new blood vessels, which is common in malignant tumours.

#### **6.6 Cardiovascular diseases**

Carotenoids have been shown to reduce oxidative stress, inflammation, dyslipidaemia, and thrombosis, which are all factors in the development of cardiovascular disease.

Carotenoids appear to restore the endothelial bioavailability of nitric oxide (NO) by purging superoxide anion (O2), which is a direct cause of reactive oxygen species (ROS) formation [62]. By oxidising LDL and lowering HDL, some carotenoids, such as astaxanthin, lutein, and beta-cryptoxanthin, are proven to be more effective at avoiding cardiovascular disease. Myocardial damage and many other conditions can be treated with this [63].

#### **6.7 Ophthalmic infections**

Rhodopsin, a component of vitamin A, is essential for the efficient conversion of light energy from pictures into electrochemical impulses, which is a crucial function of the human eye [64]. Night blindness is a result of a vitamin A deficiency; it can be avoided by taking enough carotenoids, which will enhance vision. Only 10% of the carotenoids are categorised as provitamin A and later in vitamin A.

The oxygenated carotenoids lutein and zeaxanthin, which are essential for clear, detailed vision as well as for filtering the blue light from screens and removing free radicals from the retina, are found in the macular portion of the retina. They can also assist in preventing eye cataracts and macular degeneration associated with ageing.

#### **6.8 Anti-hyperglycaemia**

Uses of carotenoids by humans decreases the risk of type2 diabetes mellitus. Astaxanthin, a well-studied carotenoid, has better antioxidant characteristics than other carotenoids such as lutein, zeaxanthin, and beta-carotene, and it has been claimed to be useful in the prevention and control of diabetes [65]. The antioxidant properties of astaxanthin can help to maintain the morphology and function of beta cells.

The main cause of hyperglycaemia is lifestyle and eating choices. Hypertension causes oxidative stress, which complicates the body by linking it to obesity, diabetes, dyslipidaemia, and hyperhomocysteinemia. Here, fatty acid radicals and (ROS) play a crucial part in raising the body's levels of GR, GPx, and other hormones that cause illnesses [66, 67]. Carotenoids restore regulatory signals to normal by scavenging fatty acid radicles and ROS [68].

#### **6.9 Skin protection**

The skin accumulates a lot of the carotenoids that are taken as part of a typical diet and uses them to defend itself from sunburn, ageing, and damage caused by UV rays [48]. Carotenoids, with their antioxidant and anti-inflammatory characteristics, as well as their capacity to regulate cell growth and division, can help protect the skin from photodamage and prevent skin disorders.

Several investigations showed that beta-carotene had a preventive effect against sunburn, or erythema, in clinical settings. The colourless carotenoids phytoene and phytofluene may also effectively shield the skin [69]. However, dietary carotenoids like lycopene or beta-carotene provide much lower levels of photoprotection than topical sunscreens do.

#### **7. Conclusion**

Carotenoids have emerged as fascinating natural compounds with significant potential for promoting public health and serving as therapeutic interventions. Their antioxidant, anti-inflammatory, immune-modulating, and photoprotective properties contribute to their diverse range of health benefits. Carotenoids have shown promise in preventing chronic diseases, supporting eye and skin health, and potentially serving as novel therapeutic agents.

However, further research is necessary to fully understand the mechanisms underlying the therapeutic activity of carotenoids, optimise their bioavailability, and establish evidence-based guidelines for their use. Rigorous clinical trials, nutrigenomic studies, and investigations into novel delivery systems are required to unlock the full potential of carotenoids for public health and therapeutic interventions [70].

Incorporating a varied and balanced diet rich in carotenoid-containing foods, along with considering the potential benefits of carotenoid supplementation under appropriate circumstances, may contribute to overall health and well-being. As scientific knowledge continues to expand, carotenoids hold promise as valuable components of preventive medicine and therapeutic strategies, offering opportunities for improving human health and reducing the burden of chronic diseases.

*Recent Advancement in Therapeutic Activity of Carotenoids DOI: http://dx.doi.org/10.5772/intechopen.112580*

### **Author details**

Anju Singh\* and Kamya Omer School of Pharmaceutical Sciences, CSJMU, Kanpur, India

\*Address all correspondence to: anjutsingh@gmail.com

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

## Significance of Carotenoids in Traditional Medicines in the Republic of Suriname (South America)

*Dennis R.A. Mans*

#### **Abstract**

Carotenoids are pigments that produce bright yellow, red, orange, and purple colors in some vegetables and fruits. These compounds play major roles in various critical functions of plants. Carotenoids are also indispensable for humans, exerting antioxidant effects and sustaining both low-light and color vision. The more than 700 different types of carotenoids can be divided into two classes: the carotenes (*e.g.*, β-carotene and lycopene) which do not contain oxygen, and the xanthophylls (*e.g.*, lutein and zeaxanthin) which contain oxygen. In addition, some carotenoids such as β-carotene and α-carotene can be converted by the human body into vitamins A; lutein, zeaxanthin, and lycopene are non-provitamin A carotenoids. The Republic of Suriname (South America) is renowned for its relatively high plant diversity which comprises about 5100 species of higher plants. Several of these plants have a relatively high content of carotenoids and are widely consumed and used as traditional medicines. In this chapter, the traditional uses of eight Surinamese fruits and vegetables rich in carotenoids have been addressed, and the pharmacological support for their traditional uses has comprehensively been dealt with. The chapter concludes with the scientific evidence to justify the traditional uses of the carotenoids in these plants.

**Keywords:** carotenoids, xanthophylls, carotenes, Suriname, fruits, vegetables, traditional medicine

#### **1. Introduction**

Carotenoids are natural pigments belonging to the class of terpenoids that produce many of the bright yellow, orange, red, and purple colors of fruits, flowers, and tubers of certain plants such as citrus fruits, peppers, tomatoes, carrots, and sweet potatoes [1]. So far, over 700 structurally different carotenoids have been identified [1], and they play several major roles in plants [2, 3]. Firstly, these compounds are essential to photosynthesis by absorbing light in the blue-green region of the solar spectrum and transferring the absorbed energy to chlorophylls, thus expanding the wavelength

range of light that enables photosynthesis [2, 3]. Furthermore, carotenoids help protect plants from photo-oxidative damage by scavenging singlet molecular oxygen and peroxyl radicals [2, 3]. These compounds also help protect plants from predation by repelling predators and attracting insects, birds, and small mammals to assist in the pollination of flowers and the dispersal of seeds [4, 5].

In addition to plants, carotenoids are produced by various other organisms including (heterotrophic) bacteria, fungi, algae, aphids, and spider mites [6]. These compounds are also responsible for the pinkish-red colors of some birds, fish, crustaceans, and insects which feed on organisms that contain carotenoids such as the red flamingo; salmon, red trout, and red sea bream; as well as shrimp, krill, crab, lobster, and crayfish [6].

Humans are unable to synthesize these compounds *de novo* and rely on the diet as a source of carotenoids [7]. As mentioned in greater detail below, these compounds play major roles in human health by functioning as precursors of vitamins A [8, 9]. Carotenoids are also important by functioning as crucial components of the exogenous defense system against reactive oxygen-derived species (ROS) [10, 11]. This chapter provides some information about the biochemistry, classification, and biosynthesis of carotenoids, gives some background on the Republic of Suriname, and then comprehensively addresses eight well-known Surinamese fruits and vegetables that are rich in carotenoids, highlighting the involvement of these compounds in the beneficial and health-promoting effects of the plants.

#### **2. Biochemistry, classification, and biosynthesis**

Carotenoids are polyunsaturated lipid-soluble tetraterpenoids consisting of a C-40 polyene backbone that is made up of eight isoprene units connected head-to-tail, except for the central unit, which has a reverse connection [6, 12]. Carotenoids can be classified into two main groups, namely carotenes and xanthophylls [6, 12]. Carotenes are unoxygenated carotenoids which typically contain only carbon and hydrogen (and are therefore placed in the subclass of unsaturated hydrocarbons), and include, among others, β-carotene, lycopene, and α-carotene [6, 12]. These compounds have in general an orange-red color [13–15]. Xanthophylls are oxygenated derivatives of these hydrocarbons, containing hydroxyl, methoxyl, carboxyl, keto, or epoxy groups, and include, among others, lutein, zeaxanthin, β-cryptoxanthin, and neoxanthin, and often have a yellow color [6, 12].

Important sources of orange-colored β-carotene are carrots (*Daucus carota* L.; Apiaceae), ripe tomato fruit (*Solanum lycopersicum* L.; Solanaceae), and ripe paprika fruit (*Capsicum annuum*; Solanaceae) [3, 16]. Lycopene contributes to the red color of ripe tomato fruit, and the xanthophyll capsanthin to that of paprika fruit (*Capsicum annuum*; Solanaceae) [3, 16]. Carrots also contain α-carotene, as does the beetroot (*Beta vulgaris* L.; Amaranthaceae) as well as mandarins (*Citrus reticulata* Blanco; Rutaceae) and oranges (*Citrus × sinensis* (L.) Osbeck; Rutaceae) [3, 16]. Fresh, darkgreen, leafy vegetables such as spinach (*Spinacia oleracea* L.; Amaranthaceae), lettuce (*Lactuca sativa* L.; Asteraceae), as well as kale and broccoli (cabbage cultivars from *Brassica oleracea* L.; Brassicaceae) also contain relatively high levels of β-carotene, in addition to lutein and zeaxanthin [3, 16]. Only a relative handful of foods contain fairly high concentrations of β-cryptoxanthin [17]. A few examples are tangerines (*Citrus tangerina* Tanaka; Rutaceae) as well as yellow and orange maize (*Zea mays* L.; Poaceae) [18]. And the pink/red coloration of marine animals such as crustaceans,

*Significance of Carotenoids in Traditional Medicines in the Republic of Suriname… DOI: http://dx.doi.org/10.5772/intechopen.113013*

shellfish, and salmon is caused by the xanthophyll astaxanthin in the plants and small animals they feed on [3, 16].

In plants, carotenoids are synthesized in the chloroplasts in the leaves through a highly conserved and ubiquitous metabolic pathway reviewed in Ref. [19]. Briefly, the pathway starts with the fusion of two C20 geranylgeranyl pyrophosphate molecules (from the upstream methylerythritol pathway) to produce the C40 tetraterpene 15-cis-phytoene (the tetraterpene skeleton). This step is catalyzed by phytoene synthase, a rate-limiting enzyme for the pathway. Next, phytoene is transformed into ζ -carotene and then into lycopene by the enzymes ζ-carotene desaturase, phytoene desaturase, and carotenoid isomerase.

The formation of lycopene represents a branch point in the pathway after which two series of products can be formed: catalysis by lycopene β-cyclase and lycopene ε-cyclase results in carotenoids with two β-rings (for example, β-carotene), and catalysis by the simultaneous actions of the lycopene cyclases generates carotenoids with one β-ring and one ε-ring (for example, α-carotene). Hydroxylation of α-carotene and β-carotene by the action of carotenoid hydroxylases results in the formation of xanthophylls such as zeinoxanthin and α-cryptoxanthin (both of which can be transformed into lutein), as well as zeaxanthin and β-cryptoxanthin, respectively. These compounds can be further converted into other xanthophylls.

#### **3. Health benefits and applications of carotenoids**

About forty structurally different carotenoids are present in a typical human diet [20]. As mentioned above, carotenoids function as precursors of vitamins A and as powerful antioxidants in the body [10, 11]. The vitamins A include vitamin A alcohols (retinols), vitamin A aldehydes (retinals), retinyl acids (retinoic acids), and retinyl esters [21]. The body obtains these preformed vitamins A through the consumption of animal products such as meat, fish, poultry, and dairy foods [22]. The body is also able to synthesize vitamins A from the provitamin A carotenoids β-carotene, β-cryptoxanthin, and α-carotene [21]. Lycopene as well as lutein and zeaxanthin are non-provitamin A carotenoids that cannot be converted into vitamins A [21]. Both latter compounds are found in the retina where they help absorb blue light and have been associated with a meaningful reduction in the risk for cataract and age-related macular degeneration [23].

In addition to their role as precursors of vitamins A, carotenoids constitute important components of the body's exogenous defenses against ROS along with several vitamins, a variety of phenolic compounds, essential minerals, small peptides, and fatty acids [10, 11]. The exogenous antioxidant defenses complement the endogenous mechanisms which comprise enzymatic antioxidant systems such as superoxide dismutase, catalase, and glutathione peroxidase [13]. Both carotenes and xanthophylls contribute to the antioxidant defenses by efficiently quenching singlet molecular oxygen and potently scavenging other ROS such as peroxyl radicals, both alone and together with other antioxidants such as vitamins A [14, 15], protecting the body against diseases associated with oxidative stress such as cancer [24], cardiovascular disease [17], and diabetes mellitus [25]. This hypothesis is supported by observational epidemiological studies mentioning that foods rich in carotenoids and antioxidant vitamins are associated with a reduced risk of these and other chronic conditions [26, 27].

Furthermore, the antioxidant properties of carotenoids are believed to improve the immune system by stimulating lymphocyte activities and cytokine production

[28]; fight skin aging, skin damage by UV light, and skin cancer by increasing density, elasticity, and firmness of the epidermis [29]; and lower the risk of dementia [30], in addition to maintaining the health of cornea and conjunctiva as well as the capacity of both low-light vision and color vision [31]. Carotenoids also elicit anti-inflammatory activities, presumably by interfering with the nuclear factor κB pathway following blockade of the translocation of nuclear factor κB to the nucleus [32]. This results in inhibition of the downstream production of inflammatory cytokines such as interleukin-8 or prostaglandin E2 [32] and is generally believed to contribute to the beneficial effects of carotenoids against the above-mentioned diseases [33].

Due to the various pharmacological activities of carotenoids, these compounds are often incorporated into dietary supplements, fortified foods, and nutraceuticals; skin care cosmetics as well as anti-aging and skin repair compounds; colorants in foods; pharmaceuticals and cosmetics; as well as animal feed additives [9, 34, 35]. For example, carotenes or β-carotene (E160a), capsanthin and capsorubin from paprika or paprika oleoresin (E160c), lycopene or tomato extract or tomato concentrate (E160d), lutein (E161b), and astaxanthin (E161j) are used as food additives in, among others, soft drinks and juices, dairy products, breakfast cereals, jams and jellies, snacks and confectionaries, as well as animal feeds [34, 35].

#### **4. The Republic of Suriname**

The Republic of Suriname is a small independent constitutional democracy located just north of the Amazon delta, bordering the Atlantic Ocean to the north, French Guiana to the east, Brazil to the south, and Guyana to the west. More than three-quarters of the country's land surface of about 165,000 km2 is part of the Amazon Basin, but Suriname is culturally considered a Caribbean rather than a Latin American country and is a member of the Caribbean Community [36]. Suriname's population is among the most varied in the world, comprising Amerindians (the original inhabitants of the country) as well as descendants from enslaved Africans, indentured laborers from Asia, and European settlers, as well as immigrants from various Latin American and Caribbean counties [37].

All ethnic groups of Suriname have preserved much of their original culture and identity, still practicing the religion they were raised with, speaking the language from their country of origin, maintaining their specific perceptions of health and disease, and adhering to their ethnopharmacological traditions [38]. As a result, the use of various forms of traditional medicine is deeply rooted in the country, despite the broad availability of affordable modern health care [38, 39]. This inclination, together with the easy access to raw plant material from Suriname's rich biodiversity, probably accounts for the frequent use of traditional herbal medications in the country, either alone or in conjunction with prescription medicines [38, 39].

#### **5. Carotenoids in eight well-known Surinamese fruits and vegetables**

Hereunder, eight vegetables and fruits with a relatively high carotenoid content that are abundantly consumed in Suriname, are in detail addressed for their traditional use. The plants include the mango *Mangifera indica* L. (Anacardiaceae), the papaya *Carica papaya* L. (Caricaceae), the water spinach *Ipomoea aquatica* Forssk.

*Significance of Carotenoids in Traditional Medicines in the Republic of Suriname… DOI: http://dx.doi.org/10.5772/intechopen.113013*

(Convolvulaceae), the sweet potato *Ipomoea batatas* L. (Convolvulaceae), the pumpkin *Cucurbita moschata* Duchesne ex Poir. (Cucurbitaceae), the avocado *Persea americana* Mill. (Lauraceae), the Suriname cherry *Eugenia uniflora* L. (Myrtaceae), and the inkplant *Renealmia alpinia* (Rottb.) Maas (Zingiberaceae). The traditional medical uses of these plants are addressed, as well as the possible pharmacological (and phytochemical) support for these uses. The relevant characteristics of the plants are given in **Table 1**.


#### **Table 1.**

*Carotenoid-containing plants in Suriname and their relevant characteristics.*

#### **5.1 Anacardiaceae:** *Mangifera indica* **L.**

The fruit of the mango tree *M. indica* has a yellow-orange-colored, juicy, and very fragrant flesh surrounded by green, yellow, or red skin depending on the variety. The color of the fruit's flesh is due to carotenoids, particularly β-carotene, while those of the peel are mainly caused by anthocyanins [98]. *M. indica* fruit contains carotenoids (mainly β-carotene), vitamins A and C, phenolic compounds (including flavonoids other than anthocyanins), volatile terpenoids, as well as various minerals [40, 41]. Preparations from *M. indica* fruit are traditionally used in Suriname for treating cardiovascular diseases such as hypertension; diabetes mellitus; respiratory ailments; gastrointestinal diseases such as worm infections and bleeding piles; parasitic infections; uterus disorders; skin problems such as warts and bleeding; varicose veins; oral and dental problems; syphilis; and poor eyesight [99].

The abundant amount of β-carotene in *M. indica* fruit represents a substantial source of vitamin A, supporting its traditional use to benefit vision [99, 100] and to lower the risk for age-related macular degeneration [45]. Some of the other traditional medical claims of the fruit (such as its positive effect on the immune system and efficacy against cardiovascular and diabetic disease) have also been attributed to the antioxidant activity of the carotenoids [42–44]. However, these health benefits have also been associated with the antioxidant activities of the phenolic compounds and vitamins A and C in the fruit [42–44, 46] and that of the phenolic compound mangiferin [101].

#### **5.2 Caricaceae:** *Carica papaya* **L.**

The unripe fruit of the papaya *Carica papaya* L. (Caricaceae) is renowned for its white latex that contains papain for meat tenderizing, clarifying American beer, and as an ingredient of detergents [102]. The latex as well as extracts from both ripe and unripe *C. papaya* fruit are also traditionally used in Suriname against hypertension; diabetes mellitus; various gastrointestinal problems including constipation, colic, intestinal worms, dyspepsia, gastritis, and gastroenteritis; hemorrhoids; to stimulate breast feeding; to maintain eye health; and/or as an abortifacient [103, 104]. Externally, fruit preparations are used for treating infected wounds and abscesses; toothache; warts, calluses, and corns; athlete's foot and ringworm; hair loss; and as a facial mask [104, 105].

Some of the ethnopharmacological uses of *C. papaya* fruit may be associated with the powerful antioxidant activities of its relatively high content of carotenoids (particularly lycopene) along with those of vitamins A, C, E, and K [47, 48]. As mentioned before, these compounds are able to neutralize ROS and reduce oxidative stress [10, 11], while lycopene also has the capacity to remove excess iron required for the production of ROS in the Haber-Weiss and Fenton reactions [106]. Thus, *C. papaya* preparations would particularly be beneficial against conditions driven by chronic inflammation such as neoplastic, cardiovascular, and diabetic disease [107]. Indeed, the consumption of *C. papaya* fruit led to a reduction of inflammatory markers including C-reactive protein in human subjects [49, 50].

These considerations may account for the reduction in oxidative stress and the beneficial effects of *C. papaya* fruit products in preventing or slowing down heart disease [108] and improving plasma HDL-to-LDL ratio [51] as well as markers of diabetes mellitus [52] and prediabetes [52, 53]. The relatively high content of zeaxanthin, along with lutein, in *C. papaya* fruit may be related to a lower risk for age-related macular degeneration [54]. And the powerful antioxidant effects of vitamin C and lycopene in *C. papaya* fruit may help prevent, delay, and repair skin damage [109].

#### **5.3 Convolvulaceae:** *Ipomoea aquatica* **Forssk.**

The water spinach *Ipomoea aquatica* Forssk. (Convolvulaceae) *I. aquatica* has a relatively high content of carotenoids including β-carotene, lutein, and violoxanthin [55]. The plant contains, furthermore, abundant amounts of phenolic antioxidants including flavonoids; vitamins A, C, and B-complex group; some alkaloids; as well as several minerals [110]. Preparations from the aerial parts of the plant are traditionally used in Suriname against diabetes mellitus; gastrointestinal problems such as constipation, jaundice, and parasitic worms; skin conditions including hemorrhoids and furuncles; heart conditions, hypertension, and anemia; as well as stress, nervousness, agitation, sleep disturbances, and psychological problems [111, 112].

Some of these traditional uses are supported by the antidiabetic effects of *I. aquatica* preparations in various preclinical models [61, 62] as well as type II diabetic patients who had been subjected to a glucose challenge [61]; their potent laxative and purgative properties [63]; and their notable central nervous system depressant [64] and anxiolytic activity in various laboratory models [65]. Furthermore, *I. aquatica* preparations displayed anti-inflammatory effects, inhibiting *in vitro* prostaglandin synthesis [60] and carrageenan-induced edema in a rat paw model [66], and showed *in vitro* antibacterial effect [66].

The potential involvement of several carotenoids in some of the pharmacological activities of *I. aquatica* is supported by the potent preclinical free radical scavenging, anti-inflammatory, and/or hypoglycemic activities of several carotenoids in preparations from its leaf and stem [56–59]. So far, however, there are no studies that firmly associate the carotenoids in *I. aquatica* with these and the other pharmacological activities of preparations from the plant. Notably, flavonoids have also been implicated in the antioxidant activities of *I. aquatica* preparations [113, 114], suggesting that the presumed beneficial effects of the plant are attributable to the combined actions of carotenoids and other classes of bioactive phytochemicals.

#### **5.4 Convolvulaceae:** *Ipomoea batatas* **L.**

The sweet potato *Ipomoea batatas* L. (Convolvulaceae) develops yellow- to browncolored and orange- to purple-colored starchy and sweet-tasting tubers with white through pink, violet, red, and purple flesh, depending on the cultivar. The different colors reflect different ratios of carotenoids versus anthocyanins in the tubers [67]. The cultivars with dark orange flesh have more β-carotene than those with lightcolored flesh [67]. *I. batatas* tuber is also rich in dietary fiber, vitamins A, C, and E, as well as manganese and potassium [68]. Preparations from several parts of *I. batatas* including the tuber are also traditionally used in Suriname for treating, among others, ophthalmological disorders such as macular degeneration and catarrh; respiratory conditions; diabetes mellitus; hypertension; gastrointestinal conditions including dysentery and constipation; abscesses; inflammation as well as arthritis and rheumatoid diseases; and cancer [104].

Particularly the orange-fleshed tuber of *I. batatas* is an important source of β-carotene [67, 68]. It is converted into vitamins A in the body [21] and all these compounds elicit antioxidant, anti-inflammatory, eye health-stimulating, immunepromoting, and other meaningful pharmacological activities [69–71, 115]. For

instance, tuber preparations seem beneficial against night blindness [116] and potentially prevented ethanol-induced gastric ulceration and stimulated wound healing [72]. These observations give some weight to several of the traditional uses of *I. batata* tuber [104].

However, the exact involvement of β-carotene in *I. batatas* (and perhaps other carotenoids) in these activities is not certain. Firstly, these compounds might cooperate with anthocyanins in decreasing the risk of colorectal cancer [117] and control blood sugar, lower LDL cholesterol, and the risk of cardiovascular diseases [69, 116]. Secondly, the antidiabetic properties of *I. batatas* preparations [118], and the inhibitory effects of "sweet potato protein" purified from the fresh tuber on the proliferation, migration, and/or invasion of human colorectal cancer in preclinical models might be attributable to certain flavonoids [119].

#### **5.5 Cucurbitaceae:** *Cucurbita moschata* **Duchesne ex Poir**

The fruit of the pumpkin *Cucurbita moschata* Duchesne ex Poir. or *Cucurbita pepo* L. var. *moschata* (Duchesne) Lam. (Cucurbitaceae) is rich in β-carotene, lutein, α-carotene, and ζ-carotene; vitamins A, B, and C; essential amino acids; and various minerals [73]. It is traditionally used in Suriname for treating poor eyesight and eye inflammation; various types of tumors; as well as hepatitis, intestinal worms, and disturbed bowel movement [104, 112, 120]. Many pharmacological studies support some of the health claims of *C. moschata* preparations such as those regarding its anti-inflammatory, antibacterial, anticancer, and deworming properties [121, 122]. Some of these studies support the involvement of carotenoids in the apparent health-promoting effects of the fruit [73]. For instance, its relatively high content of β-carotene as a source of vitamin A would provide meaningful protection of visual function and eye health [74].

The potent antioxidant activity of the carotenoids in *C. moschata* fruit [74, 75] also suggests that these preparations may be beneficial against diseases associated with oxidative stress and inflammatory processes, tentatively explaining the claims of usefulness of these substances against cancer [74]. Support for this suggestion came from the increased production of Th1 cytokines by mouse splenocytes and RAW 264.7 macrophage cells isolated from mouse spleen which had been exposed to *C. moschata* fruit preparations and β-carotene [76], and the reduction of the risk of cancer of stomach, intestine, lung, breast, and prostate by increasing the intake of *C. moschata* fruit and in this way, of several carotenoids [77, 78]. However, it should be taken into account that the results from various studies contradict this claim [122–124].

#### **5.6** *Persea americana* **Mill (Lauraceae)**

The avocado tree *Persea americana* Mill. produces fruit with smooth, creamy, and golden-green flesh when ripe and a green-, brown-, purplish-, or black-colored skin depending on the cultivar. The fruit contains carotenoids, vitamins A, B, D, and E, potassium, phytosterols including β-sitosterol, as well as an unusually high amount of fat (mostly oleic acid but also palmitic acid and linoleic acid) [125]. The fruit pulp yields an edible oil that is used for salads and dips but also in the cosmetic industry for the production of soaps, hair care products, and skin moisturizers [126]. The seed can also be processed into an oil for the bath and body care industry [127].

Preparations from *P. americana* fruit pulp and fruit peel (but also from its seed, leaf, fresh shoots, and bark) are used in Suriname against cancer, gastrointestinal

#### *Significance of Carotenoids in Traditional Medicines in the Republic of Suriname… DOI: http://dx.doi.org/10.5772/intechopen.113013*

diseases, ailments of the respiratory tract, hypertension and hypercholesterolemia, menstrual problems, high uric acid levels, skin afflictions and poor hair growth, as an aphrodisiac, and as an abortifacient [99, 104, 111, 128]. These claims are partially supported by the results from clinical studies showing that fruit pulp preparations decreased the risk of cardiovascular disease and coronary heart disease [81], produced relief in symptomatic osteoarthritis of the knee and hip [82], improved the LDL to HDL ratio in (mildly) hypercholesterolemic patients [83], and had appetitedepressant and weight-reducing properties [85].

Some of these activities have been attributed to the presence of a variety of carotenoids including β-carotene, lutein, and zeaxanthin, in the samples [79, 80]. These carotenoids displayed substantial antioxidant, antimicrobial, and anti-inflammatory activities *in vitro* [84, 86–88]. In addition, lutein seemed to play a role in the growth inhibitory effect of a *P. americana* fruit in cultured prostate cancer cell lines [89] and in the protection against eye diseases such as cataract and macular degeneration [90]. However, various reports have mentioned that phenolic compounds as well as vitamins A, D, and E in the fruit pulp [86, 125] might also contribute to its pharmacological activities [84, 86–88].

#### **5.7** *Eugenia uniflora* **L. (Myrtaceae)**

Depending on the variety, the pitanga or Suriname cherry *Eugenia uniflora* L. (Myrtaceae) produces orange, bright red, or dark purple fruit with juicy, sweet-sourtasting flesh that is very rich in lycopene, γ-carotene, and β-cryptoxanthin, as well as phenolic compounds including anthocyanins and flavonoids, vitamin C, calcium and phosphorus, and pectin [91]. Preparations from the fruit are traditionally used in Suriname against high blood pressure and heartburn; diabetes mellitus; headaches, chest colds, flu, influenza, bronchitis, a sore throat, coughs, and fevers; microbial infections; skin irritations, itching, and measles; anemia and hyperuricemia; and colics and stomachache [104, 128, 129]. Preclinical studies with *E. uniflora* fruit extracts partially supported these uses, showing meaningful antioxidant [92, 93], anti-inflammatory [94], α-glucosidase inhibitory [95], anti-hyperglycemic and antihyperlipidemic [92], and anti-aging activities [93].

These pharmacological activities have mainly been attributed to phenolic compounds in the fruit preparations—particularly anthocyanins—which are believed to help mitigate the oxidative damage associated with cardiovascular disease, diabetes mellitus, the metabolic syndrome, and skin aging [130, 131]. Furthermore, certain flavonoids in fruit extracts [91] displayed antibacterial and antifungal activity [132, 133], supporting their traditional use against microbial infections [104, 128, 129]. Unfortunately, data on the involvement of carotenoids in the pharmacological activities of *E. uniflora* fruit preparations are scant, despite the relatively high content of carotenoids in this part of the plant [91, 134]. However, at least the antidiabetic activity of these preparations may be attributable to combinations of carotenoids and anthocyanins [95].

#### **5.8 Zingiberaceae:** *Renealmia alpinia* **(Rottb.) Maas**

The inkplant *Renealmia alpinia* (Rottb.) Maas also known as *Renealmia exaltata* L. f. produces fruit with a red-colored peel when immature and turns purple-black when mature, and then contains numerous seeds embedded in a yellow-browncolored pulp. *R. alpinia* fruit pulp contains carotenoids such as β-carotene, phenolic compounds such as flavonoids and anthocyanins, and vitamin C, as well as a variety of volatile terpenoids [96]. The carotenoids contribute to the distinctive colors of the fruit pulp and peel [96, 97], and the terpenoids are mainly responsible for the characteristic flavor and fragrance of preparations from the fruit [135].

Preparations from *R. alpinia* fruit pulp (as well as those from various other parts of the plant) are traditionally used in Suriname against eye diseases; the symptoms of snake bites; microbial infections; gastrointestinal ailments; cardiovascular conditions; hematologic disorders; obstetric and gynecological problems; and convulsions during, for instance, epileptic seizures [104, 136]. Unfortunately, pharmacological studies with either crude *R. alpinia* fruit extracts or (partially) purified carotenoidrich preparations are scant. The meaningful antioxidant activities of the carotenoids [96, 97] suggest that they may be beneficial against conditions involving oxidative stress such as cardiovascular ailments [17, 26, 27], but this remains to be proven. Furthermore, when considering the role of β-carotene as a vitamin A precursor [21], *R. alpinia* fruit may be useful for treating eye diseases [21, 23], but this has also not been established yet. As well, it must be determined whether and to which extent the carotenoids collaborate with the flavonoids, anthocyanins, and vitamin C to accomplish the potential health effects of *R. alpinia* fruit [96, 97].

#### **6. Concluding remarks**

Carotenoids have two fundamental pharmacological properties which are at the basis of their many health benefits, namely their roles as precursors of vitamins A and as powerful antioxidants [10, 11]. Therefore, these compounds are involved in proper vision, fetal development and male and female reproductive health, skin health, and immune function [28–31] as well as the protection of the body from oxidative stress and various associated chronic diseases [17, 24–27]. For these reasons, the intake of carotenoid-rich foods is generally recommended for maintaining and improving health. These considerations also apply to the eight carotenoid-rich plants addressed in this chapter, namely *M. indica*, *C. papaya*, *I. aquatica*, *I. batatas*, *C. moschata*, *P. americana*, *E. uniflora*, and *R. alpinia*. The fruit, leaf, or tuber from these plants are abundantly used as highly nutritious foods in Suriname and, in addition, as important traditional medicines. Notably, besides carotenoids and vitamin A, these plant parts contain relatively high amounts of phenolic compounds such as flavonoids and anthocyanins, vitamins C and E, as well as essential minerals. Clearly, these phytochemicals substantially contribute to both the nutritional value and the pharmacological activities of the plants including their provitamin A as well as their antioxidant and anti-inflammatory activities. Therefore, it is not always clear to which degree carotenoids are involved in the latter activities and, consequently, in the potential benefits of the plants against chronic diseases. This particularly holds true for preparations from *I. batatas* tuber, *E. uniflora* fruit, and *R. alpinia* fruit. This is an unfortunate paucity when considering the widespread use of these plants as foods and traditional medicines. For these reasons, comprehensive studies about the precise involvement of carotenoids in these plants (as well as others with a relatively high content of carotenoids) are mandatory.

*Significance of Carotenoids in Traditional Medicines in the Republic of Suriname… DOI: http://dx.doi.org/10.5772/intechopen.113013*

### **Author details**

Dennis R.A. Mans Faculty of Medical Sciences, Department of Pharmacology, Anton de Kom University of Suriname, Paramaribo, Suriname

\*Address all correspondence to: dennismans16@gmail.com; dennis\_mans@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 4**

## A Perspective on Carotenoids: Z/E-Isomerization, Extraction by Deep Eutectic Solvents and Applications

*Jiahao Yu and Catherine M.G.C. Renard*

#### **Abstract**

Carotenoids are used commercially for nutraceutical products because of their low toxicity, antioxidant activity, association with a reduction in various diseases and high coloring capacity. However, low stability and bioavailability limited their applications. Alterations in the physicochemical properties of carotenoids by Z-isomerization are beneficial for their extraction and bioavailability. The main strategies applied for enhancing their Z-isomerization include adding a catalyst, especially natural or heterogeneous sulfur-containing compounds. Consumers' interest in products with carotenoids of natural origin has increased, which has emphasized a need for improved methods for their extraction from food waste. The green extraction methods for carotenoid recovery, especially using natural deep eutectic solvents combined with some novel extraction techniques showed a rapid increase and excellent application prospects. Health problems faced by the older population boost the demand for carotenoid diet supplements for skin health, anti-aging, treating eye disorders, preventing cancer (prostate) and obesity, thereby driving the growth of the carotenoids industry. However, the expansion of the carotenoid worldwide market is hampered by strict regulatory and approval standards. Relevant standards of carotenoids, especially Z-carotenoids, need to be improved.

**Keywords:** Z/E-isomerization, natural catalyst, green solvents, deep eutectic solvents, stability, bioavailability

#### **1. Introduction**

Generally, carotenoids mainly exist in the chromoplasts and chloroplasts of various plants and photosynthetic algae [1]. Noticeably, colorless carotenoids phytoene and phytofluene have still been ignored, although they are also major dietary carotenoids that are present in humans at levels comparable or superior to the color carotenoids [2]. Carotenoids (i.e., lycopene and astaxanthin) can reduce the risk of various diseases, such as cardiovascular diseases, and eye-related diseases. In addition, carotenes are also provitamin A [3]. Carotenoids are not synthesized by humans and

must be obtained through the diet. The intake of total carotenoids in European countries (median values) varies between 9.5 and 16 mg per day, in which the major food sources are vegetables, fruits, and soups. Carotenoids are also widely utilized in food, cosmetic, and pharmaceutical products, primarily due to their bioactive and color properties. These various applications have enhanced the demand for carotenoid-rich products. The global carotenoid market should reach \$2.7 billion by 2027 from \$2.0 billion in 2022 at a compound annual growth rate (CAGR) of 5.7% for the forecast period of 2022–2027 (The Global Market for Carotenoids, BCC Publishing).

Carotenoids naturally mainly exist in the all-E isomer (>90%), however, Z-carotenoid isomers are abundant in human fluids and plasma, as well as some processed products (**Figure 1**) [4]. Although the presence of Z-isomers of carotenoids in processed foods can mainly be owing to Z-isomerization reaction induced by thermal treatments or light with/without catalyst, it is also found that some

**Figure 1.** *The chemical structures of main carotenoids and their isomers.*

carotenoids can also occur naturally in Z-isomers. For example, for phytoene 15-Zphytoene (not all-E isomer) is the main isomer in carotenogenic organisms [2]. Notably, some carotenoid Z-isomers (i.e., Z-lycopene and Z-astaxanthin) have been confirmed to exhibit higher bioavailability compared to all-E-isomers [5, 6]. To improve the processing efficiency (i.e., extraction) of carotenoids, Z-isomerization has also been reported to enhance carotenoid solubility [7].

Natural commercial carotenoids are mainly obtained by extracting from various processing by-products of plants and microalgae. Considering safety and environmental protection, some studies have focused on using green solvents to extract carotenoids, including supercritical CO2, ionic liquids, edible oils, deep eutectic solvents [7]. Especially, natural deep eutectic solvents (DESs) are foreseen as the next generation solvents or solvents for the twenty-first century [8]. To efficiently extract carotenoids by DESs, some processes have been successfully developed by combining hydrophobic DESs with less viscosity such as terpene/fatty acid-based DESs, with thermal treatment and homogenization techniques (i.e., ultrasound-assisted extractions).

In the chapter, carotenoid Z/E-isomerization in different solvents without/with various catalysts, carotenoid extraction by hydrophilic and hydrophobic DESs, DES recyclability from carotenoid extracts, as well as carotenoid applications as a colorant or in nutraceutical products were outlined.

#### **2. Carotenoid Z/E-isomerization**

Z-isomerization technologies of carotenoids have recently been developed to improve their processing efficiency (i.e., extraction) and bioavailability, especially with natural catalysts in different solvents.

#### **2.1 Carotenoid Z/E-isomerization in different solvents**

Several methods using different solvents for Z-isomerization of carotenoids, such as organic solvents (i.e., ethyl acetate) and edible oils with thermal, light, and catalytic treatment have been reported [9]. Z-isomerization efficiency of carotenoids greatly depends on solvents and treatment conditions. In general, carotenoids are easily induced to Z-isomerization in dissolved state but this is often accompanied by significant oxidative degradation. How to promote Z-isomerization while inhibiting the oxidative degradation of carotenoids is one of the current research problems.

The kind of solvents has a great effect on the Z-isomerization of carotenoids. Specifically, halogen solvents (i.e., dibromoethane and chloroform) used as reaction medium could promote the Z-isomerization efficiency compared to other common organic solvents (i.e., hexane, methyl tert-butyl ether, and acetone). However, halogen solvents are typically banned to use in food and cosmetic processing owing to their high toxicity. Therefore, Generally Recognized as Safe (GRAS) solvents with low/no toxicity, such as ethanol, ethyl acetate, and vegetable oils, should be used during Z-isomerization for practical industrial application. However, it is quite difficult to achieve high Z-isomerization efficiency using these GRAS solvents with traditional heating treatments, especially processing at high temperatures also induced significant degradation of carotenoids. Therefore, a series of innovative Zisomerization techniques, combined with thermal treatment, light, and microwave

irradiation have been developed to promote carotenoid Z-isomerization. Especially, microwave irradiation treatment has been used as an efficient method for carotenoid Z-isomerization owing to rapid and uniform heating, in which the efficiency of Z-isomerization is higher with microwave irradiation than with traditional heating. In addition, a continuous and efficient carotenoid (lycopene and astaxanthin) Z-isomerization procedure in a flow reactor using supercritical ethanol or subcritical ethyl acetate was also developed [10, 11]. The continuous-flow method based on hightemperature and high-pressure processing is environmentally friendly because of its low energy consumption and the green solvents, and the reaction can also easily be controlled by changing temperature and pressure to achieve high efficiency of Z-isomerization. For example, when all-E-astaxanthin was treated in the continuousflow reactor at 200°C and 10 MPa, the total Z-isomer ratio of astaxanthin was higher than 60% in only 30 s [11]. Recently, the Z-isomerization and degradation of Lycopene in various hydrophobic natural deep eutectic solvents was also reported. The studies found that HNDES composed of thymol and menthol had the highest lycopene retention, and lycopene Z-isomerization and degradation was promoted by fatty acidbased HNDES [12].

#### **2.2 Carotenoid Z-isomerization with catalysts**

Some catalysts have been added to promote the thermal Z-isomerization of carotenoids. It was reported that iron (III) chloride, iodine-doped titanium dioxide, titanium tetrachloride, as well as disulfide compounds, isothiocyanates, and carbon disulfide, promoted Z-isomerization of carotenoids. However, most of these used catalysts, such as iodine and heavy metals, have a negative effect on the human health and the environment. Thus, safety/low toxicity and environmentally friendly catalysts should be used for industrial applications. Recently, efficient isomerization methods with some plant-derived catalysts (i.e., disulfide compounds, isothiocyanates) have received particular attention. The effect of these natural catalysts on the Z-isomerization and stability of carotenoids (i.e., lycopene and astaxanthin) has been recently reported [7, 12–14]. Especially, the addition of certain food ingredients, such as cabbage and onion, could enhance the Z-isomerization of carotenoids during the thermal processing of tomato products, and isothiocyanates and polysulfides were identified as the causative components [14, 15]. In addition, mustard and roasted sesame oils as reaction media also promoted Z-isomerization of carotenoids (i.e., lycopene and astaxanthin) compared to other vegetable oils because they contained isothiocyanates and polysulfides.

Most of catalysts such as acids (namely H+), isothiocyanates, iodine, and iron (III) chloride generally exhibit great electrophilicity, which promotes Z-isomerization of carotenoids by electrophilic components [16–18]. However, the E/Z isomerization mechanism of carotenoids induced by polysulfides (i.e., diallyl disulfide DADS) was that sulfur radical (RS•) cleaved by polysulfides plays a role [13, 14]. When lycopene was induced by DADS, formation rates of 5-Z isomers were 3–4 times higher than for 9-Z and 13-Z isomers of lycopene, and lycopene degradation was clearly inhibited [14].

Noticeably, although naturally derived sulfur-containing compounds were thought to be safe, these compounds generally present a strong odor and are homogeneously dissolved, making it difficult to isolate/recycle them from the final carotenoid product. Recently, a heterogeneous (solid) catalyst based on a column packed with isothiocyanate-functionalized silica (Si-NCS) has been developed, with the advantage

of easily separating them from the carotenoid product by filtration or centrifugation and being able to be used repeatedly [19]. This catalyst promotes carotenoid Zisomerization with high efficiency, for example when astaxanthin and lycopene solutions were heated at 50°C in presence of 10 mg/mL Si-NCS, the ratios of their total Z-isomer increased by about 50% and 80%, respectively [19]. In summary, the nonhomogeneous reaction has good application prospects with high catalytic efficiency and good safety.

#### **2.3 Z-isomerization for carotenoid extractions**

Carotenoid yield could be clearly improved by Z-isomerization pretreatments or adding catalysts during extractions because Z-isomerization of carotenoids increases their solubility. The higher extraction efficiency of lycopene (even a 4–5-fold increase) with a higher ratio of Z-lycopene isomers in the tomato pulp/powder or gar arils were obtained with supercritical CO2 (SC-CO2) [20] or with ethanol by microwave irradiation pretreatments [21–23]. About 4-fold higher yield of β-carotene was also achieved for the powder of algae *Dunaliella bardawil* rich in 9-Z isomer than that rich in all-E-isomer by extraction of SC-CO2.

The addition of natural catalysts (i.e., polysulfides and isothiocyanates) or foodstuffs with these catalysts could significantly promote the extraction of lycopene from tomato pulp or carotenoids from *Paracoccus carotinifaciens* [16, 24]. Noticeably, Z-isomerization and degradation of carotenoids were both enhanced by adding isothiocyanates; however, polysulfides could promote the Z-isomerization reaction while markedly inhibiting the degradation of carotenoids [14]. These results suggested that the addition of polysulfides was helpful to improve the extraction yield of carotenoids and Z-isomers content in the extract [13].

#### **2.4 Z-isomerization for carotenoid bioavailability**

Z-isomerization reaction can induce an obvious change in the physicochemical properties of carotenoids, leading to improved bioavailability. A series of Z-isomers of carotenoids (i.e., lycopene, astaxanthin, and lutein) have been reported to possess greater bioavailability, and even higher tissue accumulation than corresponding all-E configurations [5, 25, 26].

For example, in rats' trials fed with the diet rich in astaxanthin Z-isomers, the levels of astaxanthin in blood and some tissues (i.e., eye and skin) were higher than those from the diet containing all-E-isomer. 13Z-astaxanthin was also confirmed to possess higher bioavailability and tissue accumulation efficiency than other isomers of astaxanthin, considering that the content of 13Z-isomer of astaxanthin in blood and tissues was enhanced rather than that of the 9Z-isomer when fed with the Z-isomerrich diet [26]. However, the 9Z-isomer of astaxanthin exhibited higher cellulartransport efficiency than 13Z- and all-E configurations in the Caco-2 cell monolayers experiment [6]. Different from most colored carotenoids naturally in the all-E configuration, phytoene (PT) and phytofluene (PTF) are found primarily in the Zisomer. PT is mostly found as 15-Z-PT, and PTF is usually existed as a mixture of various isomers. PT and PTF were confirmed to have high micellization efficiency and also readily absorbed by the human body, probably because of their natural Z-isomers (i.e., 15 Z-isomer) and/or high molecular flexibility [2]. We recently found that the addition of onions (or diallyl disulfide) into tomato purees reduced the ratios of their natural Z-isomers by isomerization reaction of PT and PTF, and further decreased

their bioaccessibility during in vitro digestion [27]. In conclusion, most studies have concluded that Z-isomers of carotenoids showed higher bioavailability than their all-E configurations. Therefore, the intake of carotenoid diets rich in Z-isomers, rather than all-E configurations, is recommended in terms of carotenoid bioavailability.

#### **3. Carotenoid extractions by deep eutectic solvents**

Solvents of petrochemical origin such as hexane and acetone have been used to extract carotenoids. However, these solvents can produce toxic volatile compounds, and raise some environmental issues, as well as public health and safety concerns. Therefore, the green chemistry concept pushes some researchers to find alternative green solvents for carotenoid extraction. Supercritical CO2, edible oils, ionic liquids, and deep eutectic solvents have emerged for carotenoid extractions, free of volatile petrochemical solvents. Especially, there is an explosion in the latest 5 years in using deep eutectic solvents (DESs) for carotenoid extractions by combining with some novel extraction techniques (i.e., bead-milling, homogenization, ultrasound/ microwave-assisted, and high-pressure processing) (**Table 1**).

DESs as a kind of supramolecular green solvents, are a combination of hydrogen bond acceptors (i.e., choline salts), and hydrogen bond donors (i.e., organic acids). Compared with ionic liquid and traditional organic solvents, DESs, especially natural deep eutectic solvents, are valued for their biodegradability/low impact on the environment, economical, and ease of manufacture, and fully represent green chemistry criteria. The ability to easily customize DESs by adjusting raw materials and proportions to suit the extraction matrix is another biggest advantage. In addition, the ability to improve the stability of carotenoids combined with the intrinsic safety and edibility of natural DES components makes the mixture attractive to the food industry. These intrinsic excellent characteristics have caused a rapid increase in the extraction of carotenoids using DESs.

#### **3.1 Hydrophilic DESs with co-solvents for carotenoid extractions**

Most of the traditional DESs are polar and have high viscosity, and therefore they are not suitable for extracting carotenoids. Water and alcohols as co-solvents have been added in DESs to facilitate carotenoid extraction by lowering the viscosity of DESs [43, 44]. Compared to DMSO, yields of carotenoids (β-carotene and astaxanthin) from *P. rhodozyma* biomass were increased to about 10% when using the DES choline chloride: butyric acid (1:2) water solution (at 80% w/w) [29].

Alcohols, especially methanol and ethanol are also often used as DES co-solvent [43]. The DES choline chloride: tartaric acid (2:1) with the addition of methanol has been used for carotenoid extraction from apricot by-product (β-carotene) and shrimp heads (astaxanthin) by ultrasonic-assisted and microwave-assisted extraction [28]. The yield of β-carotene from apricot by-product with the DES was higher than astaxanthin from shrimp heads in both extraction methods. The yield of carotenoid (astaxanthin) extracted by choline chloride: tartaric acid (2:1) was also similar to that of hexane: acetone: ethanol (2:1:1) in microwave-assisted extraction. A twoaqueous phase system consisting of DESs and alcohol was prepared to extract carotenoids from pumpkin peel with cellulase by ultrasound-assisted extraction.

**DES (mole ratio) Extraction methods Source of natural products Target compounds (highest yield) References Choline-based DES** Choline chloride: tartaric acid (2:1) with methanol (80:20) Ultrasound (600 W, 5 or 10 min, 30–35°C), and Microwaveassisted (120 W, 20 min; 30 W, 7 min) extraction Apricot and shrimp wastes Carotenoids (β-carotene/ astaxanthin 761/267 μg/g dry residue) [28] Choline chloride: lactic acid (1:1) Choline chloride: lactic acid (1:2) Choline chloride: butyric acid (1:1) Choline chloride: butyric acid (1:2) aqueous solutions (at 80% w/w) Stirring at 300 rpm and 65°C for 60 min; Wet biomass of *P. rhodozyma* (at a concentration of 0.2 g/mL) β-carotene/ astaxanthin (46/48 μg/ mL wet biomass) [29] Choline chloride: oxalic acid (1:1) Choline chloride: oxalic acid (1:1) with water added (20% v/v) Choline chloride: urea (1:2) Choline chloride: urea (1:2) with water added (20% v/v) Choline chloride: glycerol (1:2) Choline chloride: glycerol (1:2) with water added (20% v/v) Stirring at 150 rpm and 50°C for 2 h *Dunaliella salina* microalgae Carotenoid (89.5%) [30] Lactic acid: glucose (5:1) Betaine: ethylene glycol (1:2) Choline chloride: citric acid (2:1) Choline chloride: glycerol (1:2) Proline: malic acid (1:1) Choline chloride: urea (1:1) DL-menthol: camphor (1:1) DL-menthol: eucalyptol (1:1) Lauric acid: octanoic acid (1:3) Stirring at 150 rpm and room temperature for 30 min Orange peel Carotenoid (168.7 mg/ 100 g fresh peel) [31] Choline chloride: triethylene glycol (1: 3) with ethanol (6: 4) Ultrasonic-assisted extraction (300 W, 40 min) Pumpkin peel Pumpkin peel pigment (2.460%) [32] **Terpene/fatty acid-based DESs** Choline-chloride: levulinic acid (2:1, 1:1, 1:2) menthol: lactic acid (2:1, 1:1, 1:2); Menthol: lactic acid (2:1, 5:1, 8:1) Shaking at 60°C for 30 min; ultrasoundassisted extraction (100 W, 10–50 min, 30–70°C) Tomato processing byproduct Lycopene (1463 μg/g powder) [33] Menthol: acetic acid (1:1) with ethanol addition Menthol: lauric Acid (2:1) with ethanol addition Stirring (200 rpm) for 180 min at room temperature Crude palm oil Carotene/βcarotene (213/ 0.052 ppm in oil) [34] Menthol: acetic acid (2:1) Menthol: lactic acid (2:1) Menthol: lauric acid (2:1) Stirring at 200 rpm for 120 min at 40°C with and without enzyme Sunflower wastes (petals and florets) Carotenoids (1449 mg/ 100 g biomass) [35]

*A Perspective on Carotenoids: Z/E-Isomerization, Extraction by Deep Eutectic Solvents… DOI: http://dx.doi.org/10.5772/intechopen.112098*



#### **Table 1.**

*Carotenoid extractions by deep eutectic solvents (DESs).*

The extraction solvent composed of DES (choline chloride/triethylene glycol (1:3)) and ethanol (6:4) showed the highest yield of 2.46% at the optimized ultrasonic extraction conditions, namely powder of 300 W for 40 min, solid/liquid ratio of 1: 40 g/mL, cellulase addition amount of 2.10% [32]. Noticeably, the yield of carotenoids from pumpkin peel decreased with the DES water content, as carotenoids are insoluble in water.

#### **3.2 Carotenoid extraction by hydrophobic DESs**

Hydrophobic DESs with less viscosity such as terpene/fatty acid-based DESs have been developed for carotenoid extraction [36, 45, 46]. Three hydrophobic DESs prepared by menthol: camphor, menthol: eucalyptol, lauric acid: octanoic acid and two hydrophilic proline: malic acid and choline chloride: urea was compared to extract carotenoids from orange peels, in which the extracts obtained with these hydrophobic DESs showed the highest values of total carotenoids, and there was no significant difference for the three hydrophobic DESs [31, 47]. DESs composed of menthol and different organic acids (lauric, acetic, and lactic) were also used for carotenoid extraction from sunflower wastes [35]. In addition, carotenoids (especially lycopene and β-carotene) from tomato pomace were also extracted by two DESs (ethyl acetate: ethyl lactate and Men-Lac) and an organic solvent mixture (n-hexane: acetone), in which the DES (ethyl acetate: ethyl lactate) with non-thermal air-drying treatment achieved the highest yields of lycopene and β-carotene [42].

DESs composed of menthol and lactic acid (Men-Lac) were reported to increase lycopene yields by ultrasound-assisted extraction due to the strong hydrophobicity, compared with choline-chloride: levulinic acid, in which Men-Lac with the ratio of 8:1 had the highest extraction efficiency [33]. This probably was due to the lower viscosity of the menthol-based DES [48]. The DES decanoic acid: dodecanoic acid was found to exhibit comparable extraction capacity for lycopene from freeze-dried tomato fruits to acetone [38]. The hydrophobic DESs based on N, N-dime-thylcyclohexylamine, and n-butanol were used to extract β-carotene from millet by grindingassisted extraction, and phenolic antioxidants were also added to improve the stability of β-carotene [49]. Furthermore, a hydrophobic DES composed of C8 and C10 fatty acids (3:1) showed high β-carotene recovery from pumpkin [37].

The recovery efficiency of different DESs toward lutein from *Scenedesmus* sp. is compared, in which the DES composed of equimolar fenchyl alcohol and thymol (Fen-Thy) had the best performance, and the lutein extraction yield by Fen-Thy was even higher than ethyl acetate [39]. The ratio of hydrogen bond acceptors and donors of Fen-Thy has a significant effect on the lutein extraction yield. For example, when their ratio was below 1:1, the yield of lutein increased with the proportion of fenchyl alcohol. Additionally, Fen-Thy also enhanced the lutein stability under high temperature and light owing to hydrogen bond and Van der Waals interaction [39].

Terpene-based DESs were used to extract astaxanthin from crab shell residues by a straightforward solid-liquid extraction method. Astaxanthin yields were 3–657-fold higher than that at 6 h Soxhlet extraction from shrimp shells, mussels, and *H. pluvialis* when operating at 60°C for 2 h using the DES menthol: myristic acid (8:1) [36]. Three DESs composed of terpenes (thymol, menthol, and geraniol) and oleic acid were used for the extraction of astaxanthin from the microalga *Haematococcus pluvialis* [40]. All the DESs produced high astaxanthin recovery rates of about 60% for dried biomass, which were higher than the values of 40% with oleic acid alone. This showed that the extraction ability of oleic acid was effectively improved when using in the form of DES with one of the three terpenes, probably owing to a reduction of oleic acid viscosity or an increase in affinity for astaxanthin by π–π stacking interactions [40]. The DESs composed of thymol and oleic acid could increase astaxanthin stability after prolonged oxidative stress due to the antioxidant properties of thymol. This hind that some DESs can stabilize carotenoids, and acted as a storage system for sensitive molecules. The capacity of improving carotenoid extraction and stability combined with the intrinsic safety and edibility of the components of natural DESs makes the formulation of carotenoid-DES extract attractive to the food ingredients/additives industry.

#### **3.3 DES recyclability from carotenoid extracts**

The recovery of DESs and isolation of target compounds from the extract remain a challenge due to their low vapor pressure. The recyclability of DESs will bring benefits in reducing the costs of extraction processes for industrial scale-up. Noticeably, the recovery of carotenoids may not be indispensable for natural DESs because most of them are thought to be safe and can be directly used in food/pharmaceutical formulations because of their inherently benign character. For example, according to the standards set by the Flavor Extract Manufacturers' Association (FEMA) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the composition of some natural DESs can be found as food additives or spices, thus these natural DES could be applied to food products. Recently, only a few studies focused on the recovery of DESs for carotenoid extractions, most did not consider recovery levels of the DESs and carotenoids.

Switchable DESs such as the DESs consisting of fatty acids were easily separated and recovered from the extract of carotenoids because the DES solvent polarity could be reversibly switched from hydrophobic to hydrophilic [50]. A switchable solvent system based on pH adjusting by a bio-friendly dilute amine solution (i.e., NH4OH) and CO2, has been developed, which mainly included: (1) switching hydrophobic to hydrophilic of DESs by adjusting pH using NH4OH or CO2 after extracting carotenoids; (2) after the polarity switching, the formed precipitate of carotenoids due to their low solubility in the hydrophilic media were separated by simple decantation or filtration; (3) recovering the DESs by pumping CO2 or NH4OH to cause a phase

splitting and further by separating by centrifugation [37, 49, 51]. This switching recovery procedure was very efficient and required minimum intervention of external or complex lab equipment, which have been applied for carotenoid separation and DES recycling. For example, switchable DES solvents based on fatty acids or the combination of N, N-dimethyl cyclohexylamine, and n-butanol have been used in their hydrophobic form to extract and separate carotenoids, such as β-carotene from millet and pumpkin samples [37, 49]. The yield of β-carotene did not decrease, and over 91.0% of β-carotene from the millet could be directly recovered each time in five DES recycling processes [49]. Noticeably, it is also possible to extract some hydrophilic compounds by using the DES in a hydrophilic form after switching by adjusting pH. In this way, both polar and nonpolar target compounds could be successively extracted and separated, and DESs could also be reused. However, further studies of the development of available protocols for applying DESs in carotenoid extractions, with respect to their performance and recovery, the stability of carotenoids, production costs, and their potential effects on human health are still required.

#### **4. Carotenoid applications**

The market of carotenoids is expanding as a result of the increased use of carotenoids as food coloring and nutritional supplements due to their bioactive (i.e., antioxidant, anti-inflammatory) benefits and vitamins, as well as significant R&D efforts to accelerate the production of high-quality carotenoids. The carotenoid market shares are mainly divided into astaxanthin, capsanthin, lutein, β-carotene, lycopene, and others (Carotenoids Market, 2021–2031, Report Code: A04670). Especially, in 2021, astaxanthin accounted for the highest market share for carotenoid products in the market. The approval of the U.S. Food and Drug Administration for the application of astaxanthin as a color additive in fish and animal food applications boosts the carotenoids market demand. Furthermore, health benefits such as maintenance of skin glow, brain health improvement, and healthy vision, as well as growing awareness regarding natural ingredients drive customer preference toward algae-based astaxanthin products, thus supporting the growth of the global market. The companies identified in the global carotenoid market mainly include BASF SE (Germany), Koninklijke DSM N.V. (The Netherlands), FMC Corporation (USA), Chr. Hansen A/S (Denmark), Kemin Industries, Inc. (USA), Lycored Ltd. (Israel), and Cyanotech Corporation (USA). An increase in the competitiveness of business entities from China (i.e., NHU Co., Ltd) and India on the global market of carotenoids has also occurred.

#### **4.1 Carotenoid as coloring agents**

Carotenoids are mainly used as colorants, one of the groups of food additives by legislations (Regulation (EC) No. 1333/2008; (China) GB2760-2014; (Canada) NOM/ ADM-0099) of different countries, in which natural coloring agents have been gaining popularity in the food sector. Carotenoids present a range of colors among intense yellow (diverse xanthophylls), orange (β-carotene), and red (lycopene). According to the standards for food additives, the dosage of common carotenoids such as lycopene, β-carotene, and lutein is different according to different food types and legislations. For example, the maximum consumption of lycopene in the standard (China) GB2760-2014 changed between 0.015 and 0.39 g/kg according to different

food types, however for the standards (EC) No. 1333/2008 and (Canada) NOM/ADM-0099, the values are 5–500 mg/kg, and 3–100 mg/kg, respectively. In the European Union, all food additives are subject to a safety evaluation by the European Food Safety Authority before they are permitted for use in the European Union by the European Commission. The European Food Safety Authority has made recommendations defining safe daily intakes of carotenoids. For example, as an additive the acceptable daily intake (ADI) for lycopene is 0.5 mg/kg body weight per day, and the value for lutein from *Tagetes erecta* is 1 mg/kg body weight per day. In addition, natural astaxanthin from *Haematococcus pluvialis* is used as a nutritional supplement with a daily recommended consumption of 12 mg per day by the U.S. Food and Drug Administration. Noticeably, *Haematococcus pluvialis* and krill oil rich in astaxanthin, as well as lutein ester from Marigold Chrysanthemum have been used as new food raw materials in China, and their maximum consumptions are 0.8 g, 3 g, and 12 mg per day, respectively. Although *Haematococcus pluvialis* and lutein ester can be used in general food without any limitation, there are clear restrictions on their use in infant food.

#### **4.2 Carotenoid as diet supplements**

The development of the market of carotenoid-containing products results from various economic, demographic, and sociocultural factors. The senior citizen segment constitutes a major portion of the population in the developed world and is the largest user of preventive and protective medication. Health problems faced by the older population such as vision damage is often associated with insufficient intake of vitamins. Balanced consumption can be observed in contemporary consumer behaviors. These are anticipated to boost the demand for carotenoid diet supplements, thereby driving the growth of the carotenoid industry. Commercial nutraceutical carotenoidbased supplements including Trunature astaxanthin, NATURE'S BOUNTY lutein, Jamieson lycopene, NOW natural beta-carotene, and NATURGIN Fucoxanthin, in the form of capsules (or soft gel) or tablets are currently available (**Table 2**). The contents of carotenoids in these carotenoid-containing products range from 1 to 100 mg/capsule (piece). The functional claim of these carotenoid-containing products mainly focuses on skin health, anti-aging, treating eye disorders, preventing heart disease, cancer (prostate), and obesity due to high antioxidant properties. Especially, the products rich in β-carotene act as diet supplements of vitamin A; astaxanthin plays a positive role in anti-aging and skin care; lutein and zeaxanthin are used to prevent ocular oxidative stress, supporting eye and retina health; lycopene helps to protect the prostate, and treat prostate disease; fucoxanthin is helpful for prevention and treatment of obesity and improving liver health.

#### **5. Conclusion**

Z-isomerization of carotenoids (i.e., lycopene and astaxanthin) can promote their extraction and bioavailability. Z-isomers of carotenoids can be applied in various health products with broad development prospects owing to its physiological activities (i.e., antioxidant, and anti-inflammatory) and high bioavailability. Thermal Zisomerization of carotenoids using natural catalysts especially sulfur-containing compounds, as well as isothiocyanate-functionalized silica was promising for the food industry. Carotenoids used in the food sector as colorants or diet supplements are






> **Table 2.** *Examples of carotenoid-containing*

 *products.* mostly extracted from various processing by-products. Traditional extraction of carotenoids using organic solvents requires an extensive downstream operation for the purification of the target carotenoids. Some natural DESs as green/safety solvents can be directly included in the final product as food additives or spices, which makes that there are two options for the use of carotenoids-DES extracts as dietary supplements in the food industry: (1) including the obtained extracts directly in food products without the elimination of DESs; (2) developing a process to isolate the target carotenoids and recycle the DES solvents. Noticeably, before carotenoids-DES extracts are directly used in food products, DESs should be guaranteed to be enough safety. In conclusion, in order to promote the development and application of carotenoids as colorants or diet supplements, food processing technologies (i.e., Zisomerization using natural catalyst, extraction by natural DESs) need to be developed to improve the content of Z-carotenoids in processed food and promote the industrial application. However, the expansion of the worldwide market for carotenoids is hampered by strict regulatory and approval standards. Relevant standards (i.e., GB2760-2014; (EC) No. 1333/2008) of carotenoids, especially Z-carotenoids, need to be improved.

#### **Acknowledgements**

This work was supported by the grants from National Natural Science Foundation of China (32302056); Zhejiang Provincial Natural Science Foundation (Q23C200037); China Postdoctoral Science Foundation (2022M712847).

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Jiahao Yu<sup>1</sup> \* and Catherine M.G.C. Renard<sup>2</sup>

1 School of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China

2 INRAE, TRANSFORM – Division of Science for Food, Bioproducts and Waste Engineering, Nantes, France

\*Address all correspondence to: yujiahao0201@163.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3
