**12. Ethanol and free radicals**

112 Liver Regeneration

for NADH reoxidation produced during ethanol metabolism by cytosolic ADH (Adachi & Ishii, 2002); in addition, it alters hepatic microcirculation by stimulating endothelial-1 production (Thurman, 1998); similarly, the acetaldehyde generated by ethanol metabolism causes hypoxia on chemically reacting with free sulfate groups such as glutathione, in such as way as to alters the reaction of this metabolite, which activates the xantine oxidase and xantine dehydrogenase enzymes, in order to finally diminish the NAD+/NADH equilibrium

Depletion of antioxidant levels, above all that of hepatic glutathione, caused by acute as well as by chronic ethanol consumption, increases oxidative stress, which induces changes in the mitochondrial membrane, such as diminution of the mitochondrial membrane potential in hepatocytes and MPT, both inhibited by the antioxidants or by an ADH inhibitor (Adachi &

When there is an important, functional hepatic mass loss, such as occurs in PH, the remnant tissue undergoes a regeneration process in which the removed tissue is replaced in its totality; during this process, DNA synthesis increases notably, reaching a maximal peak of 23 at 25 hours postsurgery. After PH, hepatic tissue become more vulnerable to the damage caused by consumption of xenobiotics, particularly ethanol administration, which causes damage to HR, above all in the early regenerative process phase (Morales-González et al.,

Studies performed in animals in which PH was carried out suggest that the acute ethanol administration rapidly inhibits the result of the HR after surgery; this has been assessed by a frank diminution of the cell proliferation parameters in the remnant liver. Although the exact mechanism by which ethanol inhibits HR, it is reasonable to assume that this hepatotoxicity could alter the total metabolism of the regenerating liver, which includes ethanol oxidation into acetaldehyde, catalyzed by ADH, and the later conversion of this into

Acute ethanol administration produces structural and biochemical changes such as partial inhibition of protein and DNA synthesis, which indicates the diminution of the mitotic index, transitory accumulation of fat, the presence of inflammation, modifications in hepatocellular organization, diminution of weight gain in the regenerating liver, and

Some physiological processes that are altered by ethanol are metabolite levels in serum (glucose, triglycerides, albumin, and bilirubin), in addition to causing modification of the serum activity of enzymes that reflect liver integrity (alanine and aspartate aminotransferase, lactate dehydrogenase, ornithine carbamoyltransferase, and glutamate dehydrogenase); also, on inhibiting DNA synthesis and the activity of enzymes intimately related with this process, such as Thymidine synthetase (TS) and Thymidine kinase (TK), in

A sole dose of ethanol is capable of significantly inhibiting the synthesis of the protein ornithine decarboxylase, in addition to causing thyrosine aminotransferase degradation, which suggests that acute ethanol consumption inhibits protein synthesis and regenerating

acetate by means of the mitochondrial ALDH (Gutiérrez-Salinas, 1999).

inhibition of hepatic regeneration (Morales-González et al., 2001).

addition to diminution of the mitotic index (Morales-González et al., 2001).

(Gutiérrez-Salinas & Morales-González, 2004).

2001; Morales-González et al., 1999).

**11. Inhibition of hepatic regeneration by ethanol** 

Ishii 2002).

One factor that suggested that ethanol causes cell damage due to its hepatic metabolism is the excessive generation of FR, which can be the result of a state denominated oxidative stress; this is because any of ethanol's metabolic pathways, principally MEOS, is made up of chemicals oxido-reduction reactions, which produce highly unstable molecules called Reactive oxygen species (ROS), such as the superoxide anion (O2 ‒ ), Hydrogen peroxide (H2O2), and the hydroxyl radical (OH•) (Nanji & French, 2003).

FR can perform four main reactions (Wu & Cederbaum, 2003):


Free radicals are chemical species that possess an unpaired electron in their last layer, which allows these to react with a high number of molecules of all types, first oxidizing these and afterward attacking their structures. If lipids (polyunsaturated fatty acids) are involved, they damage the structures rich in the latter, such as cell membranes and lipoproteins (Rodríguez et al., 2001). Within this generic concept, the partially reduced forms of oxygen are denominated Reactive oxygen species (ROS). This is a collective term that includes not only oxygen free radicals, but also some reactive non-radical oxygen derivatives.

The oxidating mechanism of FR is intimately linked to their origin, which follows a sequence of chain reactions; in these reactions, a very reactive molecule is capable of reacting with another, non-reactive molecule, inducing in the latter the formation of a FR ready to initiate a new neutrophilic attack, and so on successively.

The Protective Effect of Antioxidants in Alcohol Liver Damage 115

including ethanol. These investigations have demonstrated that glycine blocks the increase of Calcium (Ca2+) in hepatocytes, caused by agonists released during stress, such as

It is known that the early, ethanol consumption-related hepatic-damage phase is characterized by steatosis, inflammation, and necrosis, which are principally mediated by resident Kupffer cells in liver macrophages (Yin et al., 1998). Senthilkumar and colleagues (2004) in a model of ethanol-intoxicated rats administered with glycine, observed a significant diminution of total free fatty acid levels in the liver, in addition to a decrease in steatosis and necrosis after glycine administration (Senthilkumar & Nalini, 2004). In another study conducted by the same researchers, the latter demonstrate that treatment with glycine offers protection against FR-mediated oxidative stress in the membrane of erythrocytes, plasma, and

It has been reported that glycine inhibits macrophage activation and TNF-α release; this amino acid prevents liver damage after chronic exposure to ethanol and attenuates the lipoperoxidation and glutathione depletion induced by diverse xenobiotics (Mauriz et al., 2001). Kupffer cells in liver constitute 80% of the resident macrophages in the organism. Glycine blocks the systemic inflammatory process arising in a broad variety of pathological states, due to the activation of macrophages that release potent inflammatory mediators such as toxic cytokines and eicosanoids, which perform an important role in the progressive

Prior studies have demonstrated that glycine administration prevents several forms of hepatic lesions; because it prevents the necrosis and the inflammation developed in the early phase during chronic ethanol administration, glycine's mechanism of protection against damage involves the Kupffer cells (Ishizaki et al., 2004). As mentioned previously, Kupffer cell activation releases active substances such as NO, TNF-α, ROS, Interleukin β (IL-β), IL-6, and TGF, which cause potential damage to the liver; in particular, TNF-α, as a product of Lipopolysaccharide (LPS), plays an important role in the induction of hepatic damage on activating gene transcription factors of nuclear regulator cytokines such as NF-*K*B, which is related with the inflammatory response and which plays an important role in the activation

One probable hepatoprotector mechanism of glycine is due to that this amino acid activates the chloride channels, causing a diminution of intracellular Calcium,(Ca2+) concentration in the Kupffer cells, which hyperpolarize the cell membrane, rendering the opening of voltagedependent Ca2+ channels difficult; in addition to inhibiting macrophage activation and TNG-α release, glycine prevents liver damage after chronic exposure to ethanol and attenuates lipoperoxidation and hepatotoxin-induced glutathione depletion (Senthilkumar & Nalini, 2004). It is well known that intracellular Ca2+ is important for activation and release of inflammatory cytokines. TNF-α production by Kupffer cells has been associated

**14. Effect of vitamin E on liver regeneration in the presence of ethanol-**

Vitamin E is well known for its antioxidant properties; these function as rupturing the antioxidant chain that prevents the propagation of FR reactions; this protects cells from

hepatocytes of rats with ethanol-induced hepatic damage (Senthilkumar et al., 2004).

Prostaglandin E2 (PGE2) and the adrenergic hormones (Qu et al., 2002).

inflammatory response (Matilla et al., 2002).

of hepatic stellate cells (Mauriz et al., 2001).

with an increase of Ca2+ (Ishizaki et al., 2004).

**derived damage** 

The greatest source of ROS production in the cell is the mitochondrial respiratory chain, which utilizes approximately 8090% of the O2 that a person consumes; another important source of ROS, especially in the liver, is a group of Mixed function oxidase (MFO) Cytochrome P-450 enzymes. In addition to the ROS generation that takes place naturally in the organism, humans are constantly exposed to environmental FR including ROS in the form of radiation, Ultraviolet (UV) light, smoke, tobacco smoke, pesticides, and drugs utilized in the treatment of cancer (Wu & Cederbaum, 2003).

The increase in O2 ‒ and H2O2 formation is justified with the finding that in aging, electron flow conditions are modified in the transport chain of these, which is the last stage of high energy proton production, and whose passage through the internal mitochondrial membrane generates an electrical gradient that provides the energy necessary for forming ATP (5- Adenosin triphosphate). Researchers postulate that the ROS generated can produce damage to the internal mitochondrial membrane as well as to electron transport chain components or to mitochondrial DNA, which further increases ROS production and consequently, more damage to the mitochondria and an increase of oxidative stress due to increased oxidant production. FR produced during aerobic stress cause oxidative damage that accumulates and results in a gradual loss of the homeostatic mechanisms, in an interference of genetic expression patterns, and loss of cell functional capacity, which leads to aging and death.

ROS generation promotes the decrease of intracellular glutathione, elevation of cytoplasmic calcium, lipid peroxidation of the membranes, and a series of chain reactions that are accompanied by the disappearance of glycogen, decrease of ATP, and the descent of the energy state of hepatic cells; these events are the origin of membrane destruction and cell death (Thurman et al., 1999). Sustained elevation of cytoplasmic calcium is associated with activation of calcium-dependent enzymes such as phospholipase A2, glycogen phosphorylase, and the endonucleases, which cause plasmatic membrane ruptures and DNA molecule fragmentation. On the other hand, the transitory elevation of intracellular calcium intervenes in the progression of cell division in G1-to-S transitions and in those of the G2-to-M phase. Immediately after cell death, hepatocellular proliferation begins in order to re-establish cell populations that have been destroyed, thus restoring hepatic function (Andrés & Cascales, 2002).

The OH‒ radical is highly toxic for the hepatocytes, which do not possess a direct system for its elimination; this FR is produced intracellularly by two reactions that occur spontaneously and that are catalyzed by a transition metal, generally iron (Fe), which are termed the Fenton reaction and the Haber-Weiss reaction (Boveris et al., 2000).

In this reaction, Hydrogen peroxide (H2O2) in the presence of Fe as catalyzer produce the hydroxyl radical (OH•).

The superoxide radical (O2 ‒ ) leads to the formation of Hydrogen peroxide (H2O2) and both products of the partial reduction of oxygen (O2) produce the hydroxyl radical (OH•).

#### **13. Effect of glycine in hepatic regeneration in the presence of ethanol damage**

Recent studies have reported the beneficial effects of glycine, including protection against toxocity induced by anoxia and oxidative stress caused by several toxic agents for the cell,

The greatest source of ROS production in the cell is the mitochondrial respiratory chain, which utilizes approximately 8090% of the O2 that a person consumes; another important source of ROS, especially in the liver, is a group of Mixed function oxidase (MFO) Cytochrome P-450 enzymes. In addition to the ROS generation that takes place naturally in the organism, humans are constantly exposed to environmental FR including ROS in the form of radiation, Ultraviolet (UV) light, smoke, tobacco smoke, pesticides, and drugs

flow conditions are modified in the transport chain of these, which is the last stage of high energy proton production, and whose passage through the internal mitochondrial membrane generates an electrical gradient that provides the energy necessary for forming ATP (5- Adenosin triphosphate). Researchers postulate that the ROS generated can produce damage to the internal mitochondrial membrane as well as to electron transport chain components or to mitochondrial DNA, which further increases ROS production and consequently, more damage to the mitochondria and an increase of oxidative stress due to increased oxidant production. FR produced during aerobic stress cause oxidative damage that accumulates and results in a gradual loss of the homeostatic mechanisms, in an interference of genetic expression patterns,

ROS generation promotes the decrease of intracellular glutathione, elevation of cytoplasmic calcium, lipid peroxidation of the membranes, and a series of chain reactions that are accompanied by the disappearance of glycogen, decrease of ATP, and the descent of the energy state of hepatic cells; these events are the origin of membrane destruction and cell death (Thurman et al., 1999). Sustained elevation of cytoplasmic calcium is associated with activation of calcium-dependent enzymes such as phospholipase A2, glycogen phosphorylase, and the endonucleases, which cause plasmatic membrane ruptures and DNA molecule fragmentation. On the other hand, the transitory elevation of intracellular calcium intervenes in the progression of cell division in G1-to-S transitions and in those of the G2-to-M phase. Immediately after cell death, hepatocellular proliferation begins in order to re-establish cell populations that have been destroyed, thus restoring hepatic function

radical is highly toxic for the hepatocytes, which do not possess a direct system for

) leads to the formation of Hydrogen peroxide (H2O2) and both

its elimination; this FR is produced intracellularly by two reactions that occur spontaneously and that are catalyzed by a transition metal, generally iron (Fe), which are termed the

In this reaction, Hydrogen peroxide (H2O2) in the presence of Fe as catalyzer produce the

Recent studies have reported the beneficial effects of glycine, including protection against toxocity induced by anoxia and oxidative stress caused by several toxic agents for the cell,

products of the partial reduction of oxygen (O2) produce the hydroxyl radical (OH•).

**13. Effect of glycine in hepatic regeneration in the presence of ethanol** 

and H2O2 formation is justified with the finding that in aging, electron

utilized in the treatment of cancer (Wu & Cederbaum, 2003).

and loss of cell functional capacity, which leads to aging and death.

Fenton reaction and the Haber-Weiss reaction (Boveris et al., 2000).

‒

The increase in O2

(Andrés & Cascales, 2002).

hydroxyl radical (OH•).

The superoxide radical (O2

The OH‒

**damage** 

‒

including ethanol. These investigations have demonstrated that glycine blocks the increase of Calcium (Ca2+) in hepatocytes, caused by agonists released during stress, such as Prostaglandin E2 (PGE2) and the adrenergic hormones (Qu et al., 2002).

It is known that the early, ethanol consumption-related hepatic-damage phase is characterized by steatosis, inflammation, and necrosis, which are principally mediated by resident Kupffer cells in liver macrophages (Yin et al., 1998). Senthilkumar and colleagues (2004) in a model of ethanol-intoxicated rats administered with glycine, observed a significant diminution of total free fatty acid levels in the liver, in addition to a decrease in steatosis and necrosis after glycine administration (Senthilkumar & Nalini, 2004). In another study conducted by the same researchers, the latter demonstrate that treatment with glycine offers protection against FR-mediated oxidative stress in the membrane of erythrocytes, plasma, and hepatocytes of rats with ethanol-induced hepatic damage (Senthilkumar et al., 2004).

It has been reported that glycine inhibits macrophage activation and TNF-α release; this amino acid prevents liver damage after chronic exposure to ethanol and attenuates the lipoperoxidation and glutathione depletion induced by diverse xenobiotics (Mauriz et al., 2001). Kupffer cells in liver constitute 80% of the resident macrophages in the organism. Glycine blocks the systemic inflammatory process arising in a broad variety of pathological states, due to the activation of macrophages that release potent inflammatory mediators such as toxic cytokines and eicosanoids, which perform an important role in the progressive inflammatory response (Matilla et al., 2002).

Prior studies have demonstrated that glycine administration prevents several forms of hepatic lesions; because it prevents the necrosis and the inflammation developed in the early phase during chronic ethanol administration, glycine's mechanism of protection against damage involves the Kupffer cells (Ishizaki et al., 2004). As mentioned previously, Kupffer cell activation releases active substances such as NO, TNF-α, ROS, Interleukin β (IL-β), IL-6, and TGF, which cause potential damage to the liver; in particular, TNF-α, as a product of Lipopolysaccharide (LPS), plays an important role in the induction of hepatic damage on activating gene transcription factors of nuclear regulator cytokines such as NF-*K*B, which is related with the inflammatory response and which plays an important role in the activation of hepatic stellate cells (Mauriz et al., 2001).

One probable hepatoprotector mechanism of glycine is due to that this amino acid activates the chloride channels, causing a diminution of intracellular Calcium,(Ca2+) concentration in the Kupffer cells, which hyperpolarize the cell membrane, rendering the opening of voltagedependent Ca2+ channels difficult; in addition to inhibiting macrophage activation and TNG-α release, glycine prevents liver damage after chronic exposure to ethanol and attenuates lipoperoxidation and hepatotoxin-induced glutathione depletion (Senthilkumar & Nalini, 2004). It is well known that intracellular Ca2+ is important for activation and release of inflammatory cytokines. TNF-α production by Kupffer cells has been associated with an increase of Ca2+ (Ishizaki et al., 2004).

#### **14. Effect of vitamin E on liver regeneration in the presence of ethanolderived damage**

Vitamin E is well known for its antioxidant properties; these function as rupturing the antioxidant chain that prevents the propagation of FR reactions; this protects cells from

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Since its discovery, α-tocopherol has shown to possess two important functions in the membrane: the first as a liposoluble antioxidant that acts to prevent FR damage to polyunsaturated acids, and the second, as a membrane stabilizing agent, which aids in preventing phospholipid-caused lesions. It has also shown to inhibit protein kinase C (Bradford et al., 2003).

Studies *in vitro* in animals and in artificial membranes have demonstrated that tocopherols interact with polyunsaturated-lipid acyl groups, stabilizing the membranes and eliminating ROS and the subproducts of oxidative stress (Sattler et al., 2004).

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**Section 2** 

**Animal Models of Liver Regeneration** 

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