**2.2. Sources and safety of lutein**

Lutein cannot be synthesized in human and lower animals, thus it must depend on the dietary supply in nature. Lutein, along with its structure isomer zeaxanthin is present in various natural foods, including kale, spinach, brussels sprout, broccoli, corn, lettuce, green peas,

**Figure 1.** Chemical structures of macular pigments.

not able to produce lutein, they need to depend on the dietary consumption. After absorption of lutein with fat, it is attached to the lipoprotein and then transported into the circulation; subsequently, with the serum concentration of 0.2 μm, lutein reached throughout the body and accumulated in the eye, especially in the retina, to serve certain biological functions [3]. In the human eye, the distribution of lutein varies. Lutein is found in higher quantities within the peripheral retina, retina pigment epithelium (RPE), choroid and ciliary body while exhib-

According to the most updated data from WHO, 253 million people suffer from vision impairment, and 81% people who are blind or have moderate or severe vision impairment are aged 50 or above [4]. A large number of studies have indicated that lutein plays an important role in decreasing the risk of AMD, the leading cause of blindness in the elderly people in the developed countries [5, 6]. Clinical trials have demonstrated that lower concentration of lutein in retina and serum was observed in DR patients when compared with patients without diabetes [7]. Moreover, DR patients receiving lutein and zeaxanthin supplements have shown improvement in visual acuity and contrast sensitivity, indicating a possible benefit in delaying the onset and development of DR [7]. In this chapter, we will introduce the background information of lutein, summarize its functions in the normal eye, and discuss the effects of

Carotenoids are classified into two subgroups: carotenes, which are hydrophobic, consist of strictly hydrocarbons and xanthophylls, which are more hydrophilic, contain at least one oxygen atom in the polyene chain. The common characteristic of the carotenoid family is a C40H56 structure containing a long conjugated double-bound chain carrying the liner and cyclic alternatives. Lutein and zeaxanthin belong to the xanthophylls subgroup. They are characterized by the two hydroxyl groups attached to the end ionone rings in the nine conjugated carbon bounds polyene chain (**Figure 1**). The difference between lutein and its stereoisomer zeaxanthin is the position of the double bound in the terminal ring. In the human body, lutein and zeaxanthin could be transformed to each other via meso-zeaxanthin. Due to the presence of hydroxyl groups, lutein and zeaxanthin are more hydrophilic and polar in the serum and tissues, allowing them to react with oxygen produced in the liquid phase and scavenge reactive oxygen species (ROS) more efficiently. Due to the presence of chiral centers, lutein can exhibit eight stereoisomeric forms, of which (R,R,R) is mainly found in nature. On the other hand,

zeaxanthin has three stereoisomeric forms, including (R,R), (S,S), and (R,S-meso).

Lutein cannot be synthesized in human and lower animals, thus it must depend on the dietary supply in nature. Lutein, along with its structure isomer zeaxanthin is present in various natural foods, including kale, spinach, brussels sprout, broccoli, corn, lettuce, green peas,

iting low concentrations in the iris and lens [2].

lutein in age-related eye diseases.

**2.1. Chemistry and structure of lutein**

**2.2. Sources and safety of lutein**

**2. Lutein**

172 Progress in Carotenoid Research

orange pepper, kiwi fruit, orange, zucchini, and squash. Dark-green leafy vegetables are the major source of lutein, especially in kale and spinach, containing 15,800–39,550 μg/100 g and 7040–11,940 μg/100 g, respectively [1]. There are 44 and 26 mg of lutein per cup of cooked kale and spinach, respectively [8]. However, the dietary origin of lutein varies in different countries, depending on the preference for specific foods. In Canada, lutein mostly comes from spinach, broccoli, lettuce, corn, and oranges; while in Germany, spinach and green leafy salads contribute almost 50% of the total lutein supply [1]. Egg yolks, although does not contain lutein as high as kale and spinach, are treated as a great source of xanthophylls due to the high fat content in eggs, resulting in increased bioavailability. The concentrations of lutein and zeaxanthin are 292 ± 117 μg/yolk and 213 ± 85 μg/yolk (average weight of yolk is 17–19 g), respectively [9]. It has been demonstrated that consumption of 6 eggs/week increased the macular pigment optical density (MPOD) significantly, while the serum concentration of total cholesterol, triacylglycerols, high density lipoprotein cholesterol, and low density lipoprotein cholesterol stayed unaffected [10]. Because of the limitation in separating and quantifying lutein and zeaxanthin, most researches and databases frequently report the combined data of these two compounds in food. Thus, it may result in the inappropriate estimation of lutein content in several xanthophyll-rich foods (e.g. oranges and grapes). The microalgae, especially the genus Chlorella, are also an important natural source of lutein. Compared to the marigold flower, the conventional source of lutein in market, microalgae have faster growth rate and can be obtained throughout the year. Therefore, they can be used as a potential source for commercial lutein products.

According to the National Health and Nutrition Examination Survey, the intake of lutein and zeaxanthin combined is approximately 1–2 mg/day in USA [11]. In addition, German adults consume 1.9 mg/day in average and 1.4 mg/day of lutein consumption was reported for Canadians [1]. No adverse effects were reported after the supplementation of dietary lutein up to 20 mg/day for 48 weeks, 30 mg/day for 120 days, and 40 mg/day for more than 8 weeks [12–14]. Animal studies have demonstrated similar results. For rat, uptake of lutein up to 35 mg/day for 8 weeks or 208 mg/kg/day for 13 weeks, or 639 mg/kg/day was not associated with any exposure-related toxicity and adverse events [15, 16]. Thus, lutein is recognized as Generally Recognized as Safe (GRAS) by FDA. Although there is no relationship between side effects and long term, high dose supplementation of lutein, the total intake should not exceed 20 mg/day according to the report from Council for Responsible Nutrition (CRN) in 2006 [17]. Generally, the recommendation dose of lutein supplements is 10 mg/day. A recent case report has demonstrated bilateral "foveal sparkles" in an Asian woman who has taken a 20 mg/day lutein supplements together with a high consumption of dietary lutein. After 7 months of discontinuous uptake of lutein supplements but insistence of her high-lutein diet, the crystal dissolved in the right eye, but still existed in the left eye [18]. However, it is worth noting that upon the population-based surveys, consumption of lutein has gradually declined in the USA and Europe. Therefore, actions should be taken to emphasize the importance of adequate intake of carotenoid-rich food, especially from dark-green leafy vegetables.

There are several factors that affect the bioavailability of lutein and zeaxanthin, including Species of carotenoids, Linkage at molecular level, Amount of carotenoids ingested per meal, food Matrix, Effectors of carotenoid absorption and conversion, Nutrient status of the individual, Genetic factors, Host-related factors, and Interactions among these factors (short for SLAMENGHI) [20, 21]. Compared with β-carotene, the bioavailability of lutein supplied in a diet containing a large range of vegetables is much higher. The reason should be the presence of the hydroxyl groups in lutein, which makes it more polar and hydrophilic, leading to higher release of lutein into the aqueous medium. In addition, uptake of dietary fat together with lutein facilitated the formation of micelles and absorption of lutein in the gastrointestinal tract. It has been demonstrated that 3–5 g fat per meal is suitable to enhance the serum concentration of lutein [22]. However, lower bioavailability of lutein was observed when certain dietary fibers were present in foods. Sucrose polyester, a nonabsorbable fat substitute, impairs the ingestion of carotenoids such as lutein due to its preference for incorporation with nonabsorbable sucrose polyester rather than with micelles. The methods of food processing like heating, which improves release of lutein from food matrix, also influence the bioavailability of lutein. Furthermore, interactions between different types of carotenoids also affect the bioavailability. Studies have shown that lutein hampered the absorption of β-carotene, while β-carotene reduced the bioavail-

Lutein and the Aging Eye

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http://dx.doi.org/10.5772/intechopen.79604

The eye is made up of three separate layers, including the cornea and the sclera forming the outer fibrous layer; the uveal tract, which consists of the iris, ciliary body and choroid, forming the middle vascular layer; and the retina forming the inner neural tunic (**Figure 2**). In the central and posterior part of retina, there is an oval-shaped yellow area (approximately 5–6 mm in diameter) known as macula, which contains the highest concentration of photoreceptors. It is characterized by the yellow pigments that are entirely composed of lutein and zeaxanthin. The fovea, in the center of macula, is a small pit which is in charge of central vision and high-resolution visual acuity as a result of closely assembled cone cells. In addition, the retina consists of 10 layers from the outermost to the innermost, including RPE, photoreceptor cell layer, external limiting membrane (ELM), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), ganglion cell layer (GCL), nerve

Although MPs exhibit high concentration in the retina, the distribution varies in different regions of the retina. The highest concentration of MPs is observed in the fovea at about 0.1–1 mM, which is over 100-fold higher than the rest area of retina. Moreover, the ratio of lutein and zeaxanthin also differs in different parts of retina. In the peripheral retina, lutein is the major carotenoids and the ratio of lutein to zeaxanthin is 2:1, whereas the ratio is reversed

ability of lutein [20].

**3. Lutein and the eye**

**3.1. Lutein in the retina**

to 1:2 in the fovea.

fiber layer (NFL), and internal limiting membrane (ILM).

#### **2.3. Absorption, metabolism, and transport of lutein**

Since lutein and zeaxanthin are soluble in the fat, the absorption of these compounds follows a similar path like other lipophilic nutrients. After uptake of carotenoid-rich foods, xanthophylls are released from the food matrix with the aid of a variety of enzymes (e.g. esterase) and disperse in the stomach. The free xanthophylls then form micelles by incorporating with biliary phospholipids, bile salts, or dietary fats, which makes them more easily absorbed into the mucosal cells in the small intestine. Subsequently, they are transported from intestinal tract to the liver in the form of chylomicrons, where xanthophylls such as lutein and zeaxanthin are repackaged, carried by the relevant lipoproteins and released into the systemic circulation. In the circulation system, lipoproteins are responsible for transporting hydrophobic lipid including fat, plasma lipid, carotenoids, retinoids, etc. There are four types of lipoproteins: ultra-low density lipoproteins (ULDL), also known as chylomicrons; very low density lipoproteins (VLDL); low density lipoproteins (LDL); and high density lipoproteins (HDL). Compared to the non-polar carotenes such as lycopene and β-carotene, which are loaded onto VLDL and LDL, lutein and zeaxanthin are primarily transported by HDL. Both lutein and zeaxanthin are distributed in a variety of human tissues, but the distribution of them is not balanced among different tissues and organs. Retina, especially the macula, is regarded as the region where lutein, zeaxanthin, and its metabolite meso-zeaxanthin are concentrated, accounting for 25% of total carotenoids. Therefore, lutein, zeaxanthin, and meso-zeaxanthin are known as macular pigments (MPs), which play an important role in maintaining the normal functions of the eye. Although lutein is richest in the retina, it is also absorbed and distributed in other tissues such as adipose tissue in human body. It has been estimated that level of lutein in the retina was affected in obesity group, suggesting adipose tissue may compete with retina in terms of xanthophylls uptake [19].

There are several factors that affect the bioavailability of lutein and zeaxanthin, including Species of carotenoids, Linkage at molecular level, Amount of carotenoids ingested per meal, food Matrix, Effectors of carotenoid absorption and conversion, Nutrient status of the individual, Genetic factors, Host-related factors, and Interactions among these factors (short for SLAMENGHI) [20, 21]. Compared with β-carotene, the bioavailability of lutein supplied in a diet containing a large range of vegetables is much higher. The reason should be the presence of the hydroxyl groups in lutein, which makes it more polar and hydrophilic, leading to higher release of lutein into the aqueous medium. In addition, uptake of dietary fat together with lutein facilitated the formation of micelles and absorption of lutein in the gastrointestinal tract. It has been demonstrated that 3–5 g fat per meal is suitable to enhance the serum concentration of lutein [22]. However, lower bioavailability of lutein was observed when certain dietary fibers were present in foods. Sucrose polyester, a nonabsorbable fat substitute, impairs the ingestion of carotenoids such as lutein due to its preference for incorporation with nonabsorbable sucrose polyester rather than with micelles. The methods of food processing like heating, which improves release of lutein from food matrix, also influence the bioavailability of lutein. Furthermore, interactions between different types of carotenoids also affect the bioavailability. Studies have shown that lutein hampered the absorption of β-carotene, while β-carotene reduced the bioavailability of lutein [20].
