**7. Flavonoids**

106 Liver Regeneration

of T4 in active T3. Selenium, together with vitamin E, protects cells from peroxidation because the former destroys peroxides through the cytoplasm, while the latter prevents

The biological role that selenium presents is based on two fundamental properties: the antioxidant protector function from oxidative damage, and immunomodulation; in this case, it had the antecedent of a study carried out in rats in whom oxidative damage was induced and by means of Selenium (Se); a significant diminution of the enzymes aspartate aminotransferse (AST), Alkaline phosphatase (ALT), and Alanine aminotransferase (ALP) was observed, as well as an improvement in the antioxidant state. The results suggested that administration of Se to hepatic tissue protects against intoxication due to its antioxidant

Amino acids are nutrients that function as raw material for protein formation. According to their classification due to their requirement in the diet, they are classified as essential, nonessential, and semi-essential. Their most important function is the formation of peptides, structural proteins, enzymes, transporter proteins, immunoproteins, and hormones. However, each has special chemical functions in which they are exchanged or cede methyl or sulfhydroxyl groups in choline synthesis or substance detoxification. Some of these, such as glycine, cysteine, glutamic acid, or taurine, assume the role of antioxidants, and under extreme conditions when other energy sources are insufficient, these are utilized to produce energy through glyconeogenesis; each amino acid possesses different specific and concrete

This is the simplest amino acid of all, and it is one of the so-called non-essential amino acids; thus, no minimal nutritional contribution is required, given that there are substances available in the organism for its synthesis. Glycine (C2H5NO2) is produced in hepatocyte mitochondria from 3-D-phosphoglycerate, giving rise to serine, and in the presence of pyridoxal phosphate, serine hydroxymethyltransferase removes one carbon atom, thus producing glycine. It can also be constituted from carbon dioxide, ammonium, and from N5N10-methylenoTetrahydrofolate (TFH) in the same manner as in the mitochondria

Glycine is found at high concentrations in the organism, functioning as an important carbon donor for the formation of numerous essential compounds. It also functions in the biosynthesis of multiple compounds, such as the heme group, purines, proteins, nucleotides, nucleic acids, creatinine, conjugated bile salts, and porphyrins, or it can be degraded and converted into serine. In the brain, it functions as a neurotransmitter inhibitor; in addition, it serves as an extracellular communications molecule; therefore, it possesses different

Glycine possess a protector effect due to that it prevents due to that it prevents the decrease of antioxidant hepatic enzyme activity after hemorrhagic processes; this effect can be due to

peroxide formation (Manzanares-Castro, 2007).

properties (Mahfoud et al., 2010).

functions (Morales-González, 2009).

(Morales-González, 2009; Mathews-Van Holde, 1998).

antioxidant protector effects (Morales-González, 2009).

**6. Amino acids** 

**6.1 Glycine (Gli)** 

**6.1.1 Antioxidant activity** 

Flavonoids are compounds that make up part of the polyphenols and are also considered essentials nutrients. Their basic chemical structure consists of two benzene rings bound by means of a three-atom heterocyclic carbon chain. Oxidation of the structure gives rise to several families of flavonoids (flavons, flavonols, flavanons, anthocyanins, flavanols, and isoflavons), and the chemical modifications that each family can undergo give rise to >5,000 compounds identified by their particular properties (Morales-González, 2009).

Flavonoid digestion, absorption, and metabolism have common pathways with small differences, such as, for example, unconjugated/non-conjugated flavonoids can be absorbed at the stomach level, while conjugated flavonoids are digested and absorbed at the intestinal level by extracellular enzymes on the enterocyte brush border. After absorption, flavonoids are conjugated by methylation, sukfonation, ands glucoronidation reactions due to their biological activity, such as facilitating their excretion by biliary or urinary route. The conjugation type the site where this occurs determine that metabolite's biological action, together with the protein binding for its circulation and interaction with cellular membranes and lipoproteins. Flavonoid metabolites (conjugated or not) penetrate the tissues in which they possess some function (mainly antioxidant), or are metabolized (Morales-González, 2009).

#### **7.1 Silymarin**

Silymarin is a compound of natural origin extracted from the *Silybum marianum* plant, popularly known as St. Mary's thistle, whose active ingredients are flavonoids such as silybin, silydianin, and silycristin. This compound has attracted attention because of its possessing antifibrogenic properties, which have permitted it to be studied for its very promising actions in experimental hepatic damage. In general, it possesses functions such as its antioxidant one, and it can diminish hepatic damage because of its cytoprotection as well as due to its inhibition of Kupffer cell function (Sandoval, 2008).

#### **7.1.1 Antioxidant and hepatoprotector action**

Silymarin is an active principle that possesses hepatoprotector and regenerative action; its mechanism of action derives from its capacity to counterarrest the action of FR, which are formed due to the action of toxins that damage the cell membranes (lipid peroxidation), competitive inhibition through external cell membrane modification of hepatocytes; it forms

The Protective Effect of Antioxidants in Alcohol Liver Damage 109

substrate (ethanol) to the co-factor (NAD+), converting it into its reduced form, NADH; likewise, H+ acetaldehyde is transferred from acetaldehyde to NAD+. Later, the acetaldehyde oxidizes into acetate by means of the reduced Aldehyde-dehydrogenase enzyme (ALDH). Under normal conditions, acetate is converted into acetyl coenzyme A (acetyl-CoA), which enters the Krebs cycle and is metabolized into carbon dioxide and

This system is localized at hepatocyte smooth reticulum cisterns; this cytochrome P-450 2E1 dependent enzymatic system contributes to 5‒10% of ethanol oxidation in moderate drinkers, but its activity increases significantly in chronic drinkers by up to 25% (Roldán et

A critical component of MEOS is Cytochrome P-450 2E1 (CYP2E1); this enzyme catalyzes not only ethanol oxidation, but also the metabolism of other substances such as paracetamol, the barbiturates, the haloalkalines, and the nitrosamines, among others (Feldman et al., 2000).

CYP2E1 utilizes Nicotinamide adenin dinucleotide phosphate (NADP+) as a (H+) receiver for oxidizing ethanol into acetaldehyde. In this process, H+ is transferred from the substrate (ethanol) to the co-factor (NADP+), converting this into its reduced form, NADH; Similarly, the acetaldehyde is as the H+ transfers from acetaldehyde to NADP+ (Goldfrank et al., 2002). While MEOS participation is more active in the ethanol metabolism of chronic than in occasional drinkers and its relative contribution in comparison with ADH is difficult to determine, notwithstanding this, MEOS is important in the pathogeny of ethanol consumption-associated hepatic lesions because oxidation of this CYP2E1-mediated substance produces reactive oxygen intermediaries as subproducts (Feldman et al., 2000).

This presents in the peroxisomes and utilizes Hydrogen peroxide (H2O2) for ethanol oxidation; its contribution is minimal (Roldán et al., 2003). This system exists in a tight relationship with the reduced-oxidase-glutathione system and, like MEOS, is induced by chronic ethanol consumption. Ethanol oxidizes into acetaldehyde, utilizing H2O2 as coenzyme; this metabolite continues the same course as for converting into acetate through the

Any of the three ethanol pathways transforms it into acetaldehyde, which afterward is oxidized into acetate by the Aldehyde-dehydrogenase (ALDH) enzyme. Aldehyde is a

Hepatic regeneration (HR) is a process arising throughout evolution to protect animals from the catastrophic results of hepatic necrosis caused by the effect of the toxins of plants that serve them as food; this extraordinary process has been the object of the curiosity of scientists of all times. In ancient Greece, the myth of the chained Prometheus in Caucasus mountains of the Caucasus while an eagle daily devoured his entrails, which regenerated

ALDH enzyme (Morales-González et al., 2001; Morales-González et al., 1998).

highly reactive compound and is potentially toxic for the hepatocyte.

water (Goldfrank et al., 2002).

al., 2003).

**8.3 Catalase system** 

**9. Hepatic regeneration** 

**8.2 Microsomal ethanol oxidation system (MEOS)** 

a complex that impedes the entrance of toxins into the interior of liver cells and, on the other hand, metabolically stimulates hepatic cells, in addition to activating RNA biosythesis of the ribosomes, stimulating protein formation. In a study published by Sandoval et al., in 2008, the authors observed that silymarin's protector effect on hepatic cells in rats when they employed this as a comparison factor on measuring liver weight/animal weight % (hepatomegaly), their values always being less that those of other groups administered with other possibly antioxidant substances; no significant difference was observed between the silymarin group and the silymarin-alcohol group, thus demonstrating the protection of silymarin. On the other hand, silymarin diminishes Kupffer cell activity and the production of glutathione, also inhibiting its oxidation. Participation has also been shown in the increase of protein synthesis in the hepatocyte on stimulating polymerase I RNA activity. Silymarin reduces collagen accumulation by 30% in biliary fibrosis induced in rat (Boigk, 1997). An assay in humans reported a slight increase in the survival of persons with cirrhotic alcoholism compared with untreated controls (Ferenci, 1989).
