**2. Retinol (Vitamin A)**

Vitamin A, also called trans-retinol, is an isoprenoid alcohol that that performs several important functions in the organism, is essential in vision, in addition to being necessary for epithelial tissue regulation and differentiation, as well as for bone growth, reproduction, and embryonic development. Together with some carotenoids, vitamin A increases the immunitary function, reduces the consequences of infectious diseases (Goodman & Gilman, 1996), and, more recently, it has been observed that it provides certain protection against malignant diseases such as cancer (Morales-González 2009).

Vitamin A belongs to a family of similarly structured molecules that are generically denominated retinoids (low-molecular-weight molecules, derived from the hydrophobic molecules of vitamin A) (Mathews-Van Holde, 1998).

The activity of vitamin A in mammals is due not only to retinoids, but also to certain carotenes that are widely distributed in the majority of vegetables. Carotenes do not possess intrinsic vitamin A activity, but are converted into vitamin A by means of enzymatic actions that take place in the intestinal mucosa and in the liver (Morales-González 2009).

#### **2.1 Structure**

Vitamin A can present as a free alcohol, as a fatty acid ester, as an aldehyde, and as an acid (Figure 1). In this structure, on replacing the alcohol group, it obtained retinal, the principal functional form of rods and cones in the retina and, by an acid group, retinoic acid, the main functional form in cellular regulation and differentiation (Morales-González 2009; Mathews Van-Holde 1998).

#### **2.2 Digestion, absorption, and metabolism**

100 Liver Regeneration

The antioxidant defense system is composed of a group of substances that, on being present at low concentrations with respect to the oxidizable substrate, delay or significantly prevent oxygenation of the latter. Given that FR such as ROS are inevitably produced constantly during metabolic processes, in general it may be considered as an oxidizable substrate to nearly all organic or inorganic molecules that are found in living cells, such as proteins, lipids, carbohydrates, and DNA molecules. Antioxidants impede other molecules from binding to oxygen on reacting or interacting more rapidly with FR and ROS than with the remainder of molecules that are present in the microenvironment in which they are found (plasma membrane, cytosol, the nucleus, or Extracellular fluid [ECF]). Antioxidant action is one of the sacrifices of its own molecular integrity in order to avoid alterations in the remainder of vitally functioning or more important molecules. In the case of the exogenic antioxidants, replacement through consumption in the diet is of highest importance, because these act as suicide molecules on encountering FR, as previously mentioned

This is the reason that, for several years, diverse researchers have been carrying out experimental studies that demonstrate the importance of the role of antioxidants in protection and/or hepatic regeneration in animals. Thus, in this chapter, the principal antioxidants will be described that play an important role in the regeneration of hepatic cells

Vitamin A, also called trans-retinol, is an isoprenoid alcohol that that performs several important functions in the organism, is essential in vision, in addition to being necessary for epithelial tissue regulation and differentiation, as well as for bone growth, reproduction, and embryonic development. Together with some carotenoids, vitamin A increases the immunitary function, reduces the consequences of infectious diseases (Goodman & Gilman, 1996), and, more recently, it has been observed that it provides certain protection against

Vitamin A belongs to a family of similarly structured molecules that are generically denominated retinoids (low-molecular-weight molecules, derived from the hydrophobic

The activity of vitamin A in mammals is due not only to retinoids, but also to certain carotenes that are widely distributed in the majority of vegetables. Carotenes do not possess intrinsic vitamin A activity, but are converted into vitamin A by means of enzymatic actions

Vitamin A can present as a free alcohol, as a fatty acid ester, as an aldehyde, and as an acid (Figure 1). In this structure, on replacing the alcohol group, it obtained retinal, the principal functional form of rods and cones in the retina and, by an acid group, retinoic acid, the main functional form in cellular regulation and differentiation (Morales-González 2009; Mathews

that take place in the intestinal mucosa and in the liver (Morales-González 2009).

and in the prevention of damage deriving from alcohol (Burneo, 2009; Venereo 2002).

malignant diseases such as cancer (Morales-González 2009).

molecules of vitamin A) (Mathews-Van Holde, 1998).

(Venereo, 2002).

**2.1 Structure** 

Van-Holde 1998).

**2. Retinol (Vitamin A)** 

Because vitamin A is a liposoluble vitamin, retinol digestion and absorption is intimately linked to that of lipids. Retinol esters dissolved in fat from the diet arrive in the small intestine, forming micelles with the aid of bile salts. Later, hydrolysis is produced in which the pancreatic lipase enzyme participates, acting on formed micelles, causing the absorption of 90% of dietary fats. Vitamin A, together with the additional products of enzymatic hydrolysis, enter the enterocyte after passing through the cellular membrane, whether by facilitated diffusion or passively depending on the concentrations present (Morales-González 2009).

**Retinol**

Fig. 1. The chemical structure of vitamin A is made up of a 6-carbon-atom cyclic nucleus with an 11-carbon side-chain.

Carotenes as such are absorbed passively, and once in the cytoplasm, are transformed into retinol. Within the intestinal cell, the greater part of the retinol is esterified with saturated fatty acids such as palmitic acid and is incorporated in lymphatic kilomicrons, which enter into the bloodstream and are transported to the liver, where it is stored in parenchymatous cells and in the adiposites in the form of retinyl ester. The greater part of this is taken up by the hepatocytes of kilomicron fragments and is transferred in the form of light retinol to the Retinol binding protein (RBP) and toward the Kupffer cells, whose main function appears to be storage of these. When the tissues require retinol, this is transported by means of RBP and Transthyretin (TTR, prealbumin) for transport in the circulation of the target cells. The tissues are capable of taking this up through surface receptors, where the retinol is transferred to a retinol membrane binding protein and becomes a retinyl ester. Later, a hydrolase related with the membrane unfolds the latter. RBP exists in nearly all tissues; the exceptions comprise cardiac and skeletal muscle. In addition to its uptake of retinol, the RBP functions as a reservoir for cellular retinol and releases the vitamin to the appropriate sites for its conversion into active compounds. In the retina, retinol becomes 11-cis-retinal, which is incorporated into the rhodospin. In other target tissues, retinol apparently is oxidized into retinoic acid, which is transported to the nucleus. It is noteworthy that the RBP plasma concentration is crucial for regulation of the retinol in plasma and its transport to the tissues (Morales-González, 2009). In general, within the organism retinol can follow three processes; esterification and storage in the liver; conversion into active metabolites (retinal), and/or catabolism and excretion as retinoic acid (Allende-Martínez 1997).

The Protective Effect of Antioxidants in Alcohol Liver Damage 103

Vitamin C absorption is carried out in the small intestine by sodium-dependent active transport (faster and more efficient), or by passive transfusion through a glucose transporter (insulin). L-dehydroascorbic acid is more easily absorbed than L-ascorbic acid. This characteristic is attributed to that the oxidized form of the vitamin remains with ionization to the physiological pH and to that the molecule is slightly hydrophobic, which permits it to penetrate into the membranes, Once inside, it is reduced to ascorbate; in this manner, it circulates mainly in plasma and in suprarenal glands and hypophysis. The effectiveness of the absorption depends on the dose administered, because it has been observed that on increasing the dose, the effectiveness of the absorption diminishes (Morales-González, 2009).

Fig. 2. The chemical structure of vitamin C corresponds to that of a lactone; L-ascorbic acid presents a double connection link between the 2 and 3 carbon; this characteristic allows the molecule to donate electrons from this double link, forming L-dehydroascorbic acid, or in a

Similar to vitamin A, vitamin C is a natural antioxidant characterized by the capacity to donate two electrons from its double link at positions two and three, in such as way that it interacts with FR, blocking their harmful effect; consequently, it is oxidized. In addition to exerting an effect on FR, it also acts by regenerating oxidized antioxidants such as αtocopherol and β-carotene. In a study published by Ramírez-Farías et al., in 2008, the author concluded that administration of vitamins C and E provided a protector effect against liver damage; they attenuate lipid peroxidation, and both vitamins present a significantly greater effect than vitamin A against ethanol-mediated toxic effects during hepatic regeneration.

Vitamin E (C29H50O2) is known as the generic of a derived set of tocols, with α-tocopherol the most active form for humans. Tocopherols possess a functional phenolic group in a chromanol ring and an isoprenoid side- chain of 16 carbons; it is saturated with three double links. There are two groups of compounds with vitamin E activity, and the tocopherols (with a 16-carbon isoprenoid side-chain) and the tocotrienols (with the same 16-carbon chain, but with three double links); both groups present vitameres that differ in the number

**3.1 Absorption** 

reversible reaction.

**4. Vitamin E** 

**3.2 Antioxidant action** 

#### **2.3 Antioxidant action**

Vitamin A is a natural antioxidant that prevents cellular aging, eliminates FR, and protects the DNA in its mutagenic action. β-carotene is also a powerful antioxidant. We must clarify that this antioxidant function is only obtained in foods that were submitted to cooking for at least 5 minutes. Some studies have demonstrated that β-carotene supplemented in the diet has shown some evidence of antitumor action (Allende-Martínez 1997).

On the other hand, in the case of its participation in the regeneration of hepatic cells in alcohol-induced damage, a positive result is obtained, because vitamin A has shown a lesser protector effect against the formation of FR in the reversion of the hepatic regeneration inhibition caused by ethanol consumption, due to that retinol is the principal component of vitamin A, that it is an alcohol, and that retinol as well as ethanol utilize the same enzymatic pathways; thus, storage of vitamin A and of ethanol in hepatic cells is altered. Therefore, an excess of vitamin A and its interaction with the alcohol increase the capacity to produce fibrous tissue that, in the long term, can cause a cirrhosis (Ramírez-Farías et al., 2008). Thus, it is considered that vitamin A can generate, instead of a benefit, a hepatotoxicity with subsequent inflammation, necrosis, and the increase of some serum enzymes (Morales-González, 2009).
