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Overview: How Is Alcohol
Metabolized by the Body?
Samir Zakhari, Ph.D.
SAMIR ZAKHARI, PH.D., is director, Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver; interaction between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; changes in the ratio of NADH to NAD+^ (i.e., the cell’s redox state); tissue damage; fetal damage; impairment of other metabolic processes; cancer; and medication interactions. Several issues related to alcohol metabolism require further research. K EY WORDS : Ethanol-to acetaldehyde metabolism; alcohol dehydrogenase (ADH); aldehyde dehydrogenase (ALDH); acetaldehyde; acetate; cytochrome P450 2E1 (CYP2E1); catalase; reactive oxygen species (ROS); blood alcohol concentration (BAC); liver; stomach; brain; fetal alcohol effects; genetics and heredity; ethnic group; hypoxia
T
he effects of alcohol (i.e., ethanol) on various tissues depend on its concentration in the blood (blood alcohol concentration [BAC]) over time. BAC is determined by how quickly alcohol is absorbed, distributed, metabolized, and excreted. After alco hol is swallowed, it is absorbed primar ily from the small intestine into the veins that collect blood from the stom- ach and bowels and from the portal vein, which leads to the liver. From there it is carried to the liver, where it is exposed to enzymes and metabolized. The rate of the rise of BAC is influ enced by how quickly alcohol is emp- tied from the stomach and the extent of metabolism during this first pass through the stomach and liver (i.e., first-pass metabolism [FPM]). BAC is influenced by environmen- tal factors (such as the rate of alcohol drinking, the presence of food in the stomach, and the type of alcoholic bev erage) and genetic factors (variations in the principal alcohol-metabolizing enzymes alcohol dehydrogenase [ADH] and aldehyde dehydrogenase [ALDH2]).
The alcohol elimination rate varies widely (i.e., three-fold) among individ- uals and is influenced by factors such as chronic alcohol consumption, diet, age, smoking, and time of day (Bennion and Li 1976; Kopun and Propping 1977). The consequent deleterious effects caused by equivalent amounts of alco- hol also vary among individuals. Even after moderate alcohol consumption, BAC can be considerable (0.046 to 0.092 gram-percent [g%]; in the 10- to 20-millimolar^1 [mM] range). Alcohol readily diffuses across membranes and distributes through all cells and tissues, and at these concentrations, it can acutely affect cell function by interacting with certain proteins and cell membranes. As explained in this article, alcohol metabolism also results in the genera tion of acetaldehyde, a highly reactive and toxic byproduct that may contribute to tissue damage, the formation of damaging molecules known as reactive oxygen species (ROS), and a change in the reduction–oxidation (or redox)
state of liver cells. Chronic alcohol con- sumption and alcohol metabolism are strongly linked to several pathological consequences and tissue damage. Understanding the balance of alcohol’s removal and the accumulation of poten tially damaging metabolic byproducts, as well as how alcohol metabolism affects other metabolic pathways, is essential for appreciating both the short-term and long-term effects of the body’s response to alcohol intake.
Alcohol Metabolism
Although the liver is the main organ responsible for metabolizing ingested alcohol, stomach (i.e., gastric) ADH has been reported to contribute to FPM. The relative contribution of the stom ach and the liver to FPM, however, is controversial. Thus, whereas FPM is
(^1) A millimole represents a concentration of 1/1,000 (one thousandth) molecular weight per liter (mol/L).
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attributed predominantly to the stom ach (Lim et al. 1993; Baraona 2000), other previous studies (Lee et al. 2006) stress the role of the liver. Human ADH3, which is present in the liver and stomach, metabolizes alcohol poorly at physiological BACs (i.e., 0. g% BAC [or <50 mM]) in the liver but may play an important role in FPM in the stomach, because gastric alcohol concentrations can reach molar range during alcohol consumption (Baraona et al. 2001; Lee et al. 2003). However, Crabb (1997) pointed out the insuffi ciency of gastric ADH to account for FPM, so this remains unresolved. Alcohol also is metabolized in nonliver (i.e., extrahepatic) tissues that do not contain ADH, such as the brain, by the enzymes cytochrome P450 and catalase (see below). In general, alcohol meta bolism is achieved by both oxidative pathways, which either add oxygen or
remove hydrogen (through pathways involving ADH, cytochrome P450, and catalase enzymes), and nonoxidative pathways.
Oxidative Pathways
As shown in Figure 1, ADH, cytochrome P450 2E1 (CYP2E1), and catalase all contribute to oxidative metabolism of ethanol.
ADH. The major pathway of oxidative metabolism of ethanol in the liver involves ADH (present in the fluid of the cell [i.e., cytosol]), an enzyme with many different variants (i.e., isozymes). Metabolism of ethanol with ADH pro duces acetaldehyde, a highly reactive and toxic byproduct that may con tribute to tissue damage and, possibly, the addictive process. As shown in
Table 1, ADH constitutes a complex enzyme family, and, in humans, five classes have been categorized based on their kinetic and structural properties. At high concentrations, alcohol is elim inated at a high rate because of the presence of enzyme systems with high activity levels ( K m),^2 such as class II ADH, β 3 -ADH (encoded by^ ADH and ADH1B genes, respectively) and CYP2E1 (Bosron et al. 1993). This oxidation process involves an interme diate carrier of electrons, nicotinamide adenine dinucleotide (NAD+), which is reduced by two electrons to form NADH. As a result, alcohol oxidation generates a highly reduced cytosolic environment in liver cells (i.e., hepato cytes). In other words, these reactions (^2) K m is a measurement used to describe the activity of an enzyme. It describes the concentration of the substance upon which an enzyme acts that permits half the maxi mal rate of reaction.
246 Alcohol Research & Health
Figure 1 Oxidative pathways of alcohol metabolism. The enzymes alcohol dehydrogenase (ADH), cytochrome P450 2E (CYP2E1), and catalase all contribute to oxidative metabolism of alcohol. ADH, present in the fluid of the cell (i.e., cytosol), converts alcohol (i.e., ethanol) to acetaldehyde. This reaction involves an intermediate carrier of electrons,+ nicotinamide adenine dinucleotide (NAD ), which is reduced by two electrons to form NADH. Catalase, located in cell bodies called peroxisomes, requires hydrogen peroxide (H 2 O 2 ) to oxidize alcohol. CYP2E1, present predominantly in the cell’s microsomes, assumes an important role in metabolizing ethanol to acetaldehyde at elevated ethanol concen trations. Acetaldehyde is metabolized mainly by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria to form acetate and NADH. ROS, reactive oxygen species.
FAEE synthase
Ethanol
Fatty acid ethyl ester (FAEE)
Phosphatidyl ethanol
Tissue injury
Interferes with PLD-dependent signaling?
PLD
Figure 2 Ethanol is nonoxidatively metabolized by two pathways. A reaction catalyzed by the enzyme fatty acid ethyl ester (FAEE) synthase leads to the formation of molecules known as FAEEs. A reaction with the enzyme phospholipase D (PLD) results in the formation of a phospho lipid known as phosphatidyl ethanol.
PLD has a high K m for ethanol, and the enzymatic reaction does occur pre dominantly at high circulating alcohol concentrations. The product of this reaction, phosphatidyl ethanol, is poorly metabolized and may accumulate to detectable levels following chronic con sumption of large amounts of alcohol, but its effects on the cell remain to be established. However, the formation of phosphatidyl ethanol occurs at the expense of the normal function of PLD, namely to produce PA, resulting in inhibited PA formation and disruption of cell signaling. Oxidative and nonoxidative pathways of alcohol metabolism are interrelated. Inhibition of ethanol oxidation by com pounds that inhibit ADH, CYP2E1, and catalase results in an increase in the nonoxidative metabolism of alcohol and increased production of FAEEs in the liver and pancreas (Werner et al. 2002).
Genetic Aspects of
Alcohol Metabolism
Variations in the rate of alcohol absorp tion, distribution, and elimination con tribute significantly to clinical conditions observed after chronic alcohol con
sumption. These variations have been attributed to both genetic and environ mental factors, gender, drinking pattern, fasting or fed states, and chronic alcohol consumption. The following section will focus on the relevant genetic factors.
Genetic Variation in ADH and ALDH Class I ADH and ALDH2 play a central role in alcohol metabolism. Variations in the genes encoding ADH and ALDH produce alcohol- and acetaldehyde-metabolizing enzymes that vary in activity. This genetic variability influences a person’s susceptibility to developing alcoholism and alcohol-related tissue damage.
ADH. The ADH gene family encodes enzymes that metabolize various sub stances, including ethanol. The activity of these enzymes varies across different organs (see Table 1). When ethanol is present, the metabolism of the other substances that ADH acts on may be inhibited, which may contribute to ethanol-induced tissue damage. As shown in Table 1, genetic varia tion (i.e., polymorphism) occurs at the ADH1B and ADH1C gene locations
(see Agarwal 2001), and these different genes are associated with varying levels of enzymatic activity. The ADH1B variations (i.e., alleles) occur at differ ent frequencies in different populations. For example, the ADH1B*1 form is found predominantly in Caucasian and Black populations, whereas ADH1B* frequency is higher in Chinese and Japanese populations and in 25 percent of people with Jewish ancestry. ADH1C*1 and ADH1C*2 appear with roughly equal frequency in Caucasian populations (Li 2000). People of Jewish descent carrying the ADH1B*2 allele show only marginally (<15 percent) higher alcohol elimination rates com pared with people with ADH1B* (Neumark et al. 2001). Also, African Americans (Thomasson et al. 1995) and Native Americans (Wall et al.
- with the ADH1B*3 allele metabolize alcohol at a faster rate than those with ADH1B*1.
ALDH. Several isozymes of ALDH have been identified, but only the cyto solic ALDH1 and the mitochondrial ALDH2 metabolize acetaldehyde. There is one significant genetic poly morphism of the ALDH2 gene, result ing in allelic variants ALDH2*1 and ALDH2*2, which is virtually inactive. ALDH2*2 is present in about 50 per cent of the Taiwanese, Han Chinese, and Japanese populations (Shen et al.
- and shows virtually no acetalde hyde metabolizing activity in vitro. People who have one (i.e., heterozy gous) or especially two (i.e., homozy gous) copies of the ALDH2*2 allele show increased acetaldehyde levels after alcohol consumption (Luu et al. 1995; Wall et al. 1997) and therefore experi ence negative physiological responses to alcohol. Because polymorphisms of ADH and ALDH2 play an important role in determining peak blood acetaldehyde levels and voluntary ethanol consump tion (Quintanilla et al. 2005), they also influence vulnerability to alcohol depen dence. A fast ADH or a slow ALDH are expected to elevate acetaldehyde levels and thus reduce alcohol drinking. These polymorphisms and their signifi-
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Alcohol Metabolism and the Body
cance are discussed in the article in this issue by Quertemont and Didone. ADH and ALDH isozyme activity also influences the prevalence of alcohol- induced tissue damage. Alcoholic cir rhosis is reduced more than 70 percent in populations carrying the ALDH2* allele (Chao et al. 1994; Nagata et al. 2002). In a review of studies, Yokoyama and Omori (2003) reported a positive correlation between genetic polymor phisms for low-activity ADH and ALDH and esophageal and head and neck cancers. In another study (Hines et al. 2001), moderate drinkers who are homozygous for the slow-oxidizing ADH1C*2 allele, and therefore who are expected to drink at higher levels than those with the ADH1C*1 allele, showed a substantially decreased risk of heart attack (i.e., myocardial infarction). The authors (Hines et al. 2001, p. 549) only differentiated drinkers versus nondrinkers at one drink per day (“Men who con sumed at least one drink per day and were homozygous for the gamma allele had the greatest reduction in risk [relative risk 0.14]”). Interestingly, elevated acetaldehyde levels induced by ALDH inhibitors were shown to protect against alcohol- induced liver injury in experimental animals (Lindros et al. 1999) and to reduce the release of a signaling molecule (i.e., cytokine) called tumor necrosis factor alpha (TNF-α) from Kupffer cells (Nakamura et al. 2004). This finding is quite contradictory to the belief that acetaldehyde plays a role in liver damage. In a meta-analysis of most studies in the literature, Zintzaras and colleagues (2005) found that nei ther ADH nor ALDH alleles were sig nificantly associated with liver cirrhosis.
Genetic Variation in CYP2E
Although several CYP2E1 polymor phisms have been identified, only a few studies were undertaken to determine the effect on alcohol metabolism and tissue damage. In one study (Ueno et al. 1996), the presence of the rare c allele was associated with higher alco hol metabolism in Japanese alcoholics but only at high BACs (0.25 g/dL). Raimondi and colleagues (2004) re
ported that study participants with a polymorphism of CYP2E1 (CYP2E RsaI) were more likely than others to be lifetime abstainers at age 68 or older. Burim and colleagues (2004) found an association between having the m2/m CYP1A1 gene and alcoholic liver cir rhosis and the Val/Val GSTP1 (gluta thione S -transferase) gene and chronic pancreatitis.
Consequences of Alcohol
Metabolism
The different pathways of ethanol metabolism described above have numerous detrimental consequences that contribute to the tissue damage and diseases seen in alcoholic patients. These consequences include oxygen deficits (i.e., hypoxia) in the liver; inter action between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; and changes in the ratio of NADH to NAD+^ (i.e., the cell’s redox state [see Glossary]). These con sequences and the way they contribute to tissue damage and disease will be discussed in the following sections.
Hypoxia As mentioned earlier, the main path way of alcohol metabolism, which involves ADH and ALDH, results in the generation of NADH. The NADH then is oxidized by a series of chemical reactions in the mitochondria (i.e., the mitochondrial electron transport sys tem, or respiratory chain), eventually resulting in the transfer of electrons to molecular oxygen (O 2 ), which then binds protons (H+) to generate water (H 2 O). To have enough oxygen avail able to accept the electrons, the hepato cytes must take up more oxygen than normal from the blood. Consistent with this assumption, studies have shown that ethanol metabolism tends to increase the hepatocytes’ oxygen uptake from the blood (Tsukamoto
and Xi 1989). If the hepatocytes that are located close to the artery supplying oxygen-rich blood to the liver take up more than their normal share of oxy gen, however, not enough oxygen may be left in the blood to adequately supply other liver regions with oxygen. Indeed, strong evidence suggests that alcohol consumption results in significant hypoxia in those hepatocytes that are located close to the vein where the cleansed blood exits the liver (i.e., in the perive nous hepatocytes) (Arteel et al. 1996). The perivenous hepatocytes also are the first ones to show evidence of dam age from chronic alcohol consumption (Ishak et al. 1991), indicating the potential harmful consequences of hypoxia induced by ethanol metabolism. In addition to directly increasing hepatocytes’ oxygen use as described above, ethanol indirectly increases the cells’ oxygen use by activating Kupffer cells in the liver. When these cells become activated, they release various stimulatory molecules. One of these molecules is prostaglandin E2, which stimulates the metabolic activity of hepatocytes—that is, it induces them to break down and synthesize many essential molecules through a variety of chemical reactions that also require oxygen. As a result, alcohol-induced Kupffer cell activation also contributes to the onset of hypoxia.
Adduct Formation Ethanol metabolism by ADH and CYP2E1 produce reactive molecules, such as acetaldehyde and ROS, that can interact with protein building blocks (i.e., amino acids) and other molecules in the cell to form both sta ble and unstable adducts (see Table 2).
Acetaldehyde Adducts. Acetaldehyde interacts with certain amino acids in proteins (e.g., lysine, cysteine, and some of a group of amino acids called aromatic amino acids). However, not all amino acids in all proteins are equally likely to interact with acetaldehyde, and certain proteins seem to be partic ularly susceptible to forming adducts with acetaldehyde. These include the following (Tuma and Casey 2003):
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Alcohol Metabolism and the Body
cells in the liver. Both acute and chronic alcohol consumption can increase ROS production and lead to oxidative stress though a variety of pathways, includ ing, but not limited to, the following (Wu and Cederbaum 2003):
- Changes in the cells’ redox state (i.e., in the ratio of NADH to NAD+) as a result of ethanol metabolism by ADH and ALDH, which results in production of more NADH.
- Acetaldehyde formation.
- Induction of CYP2E1 at high alco hol levels.
- Hypoxia related to alcohol metabolism.
- Alcohol-induced damage to the mitochondria.
- Activation of Kupffer cells.
- Reduction of the levels of certain antioxidants (e.g., mitochondrial and cytosolic glutathione).
- Formation of the 1-hydroxyethyl radical mentioned above.
The relative contributions of these factors to the increase in ROS levels is unknown (Bailey 2003). Regardless of how they were generated, however, increases in ROS levels have numerous detrimental effects. For example, ROS stimulate the release of TNF-α from Kupffer cells. This cytokine plays an important role in activating inflamma tory reactions that can contribute to tissue damage and scar tissue formation (i.e., fibrosis) in the liver. In addition, ROS can interact with lipids, proteins, and DNA in a process called peroxida tion, which can have harmful conse quences. For example, as described in the previous section, lipid peroxidation leads to the generation of MDA and HNE. Peroxidation of mitochondrial membranes alters the membranes’ properties (e.g., membrane permeabil ity) so that certain molecules that nor mally are contained in the mitochon
dria can escape the mitochondria into the cytosol. The release of a compound called cytochrome c into the cytosol, for example, induces a chain of bio chemical reactions that ultimately causes a certain type of cell death (i.e., cell suicide, or apoptosis). Moreover, peroxidation of molecules in the mito chondrial membranes alters the distri bution of electrical charges across the membrane, which results in reduced levels of ATP in the cell and promotes another type of cell death called necro sis. Both apoptosis and necrosis con tribute to alcohol-related liver damage. To prevent or ameliorate the harm ful effects caused by ROS, researchers have studied the effects of antioxidant administration. These studies found that replenishment of glutathione by administering the glutathione precursor S -adenosyl-L-methionine (SAMe) or the use of other antioxidants attenu ated alcohol-induced liver damage (see Wu and Cederbaum 2003).
Changes in NADH/NAD+^ Levels and Gene Activation NADH and NAD+^ are involved in many important cellular reactions, and the levels of the two compounds in the cell, as well as their ratio, in many cases determines the rate at which these cel lular reactions can proceed. The ratio of NADH to NAD+^ frequently fluctu ates in response to changes in metabo lism. Ethanol oxidation, as mentioned before, results in a significant increase in the hepatic NADH/NAD+^ ratio in both the cytosol and mitochondria (Cunningham et al. 1986; Bailey and Cunningham 1998). In the cytosol, the conversion of ethanol to acetaldehyde by ADH generates NADH, the reduc ing equivalents of which are then trans ported into the mitochondria by molecules known as the malate–aspar tate shuttle. In the mitochondria, most of the NADH is produced by ALDH. Through both of these pathways, ethanol oxidation vastly increases the availability of NADH to the electron transport chain in the mitochondria. In addition to its many effects on biochemical reactions, the NADH/ NAD+^ ratio also may affect the activity
(i.e., expression) of certain genes. For example, studies of the effects of reduced food intake (i.e., caloric restric tion) on gene expression found that under conditions of caloric restriction, NAD+^ levels may act as a sensor that regulates the activity of certain genes (Imai et al. 2000). Activation of those genes, in turn, has been shown to extend the lifespan in a wide variety of organisms and to reduce the incidence of age-related diseases, such as diabetes, cancer, immune deficiencies, and car diovascular disorders (Bordone and Guarente 2005). Changes in the NADH/NAD+^ ratio resulting from ethanol metabolism might likewise influence gene expression.
Tissue Damage, Metabolic
Derangements, and Disease
Associated With Ethanol
Metabolism
Tissue Damage The direct actions of alcohol (e.g., dis ordering of membrane components and effects on signaling proteins) and the indirect effects resulting from ethanol metabolism described in the previous sections act in concert to induce tissue damage. In fact, ethanol meta bolism often is considered to be the predominant factor causing alcohol- associated tissue damage, particularly through the generation of ROS and oxidative stress in the tissues. ROS are generated during ethanol and acetalde hyde oxidation both by ADH/ALDH and by CYP2E1. The rate of ethanol and acetaldehyde oxidation by ADH and ALDH is determined by the rate with which the NADH generated can pass through the mitochondrial elec tron transport system. Because the mitochondrial electron transport sys tem requires oxygen and generates ATP, the rate of NADH oxidation depends both on the cell’s oxygen sup ply and on its demand for ATP. If either of these two factors is limited, electron transport activity is reduced. This has two effects: First, ethanol and acetaldehyde are inefficiently metabo-
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lized, and, second, electrons passing through the mitochondrial electron transport chain are “diverted” into forming harmful ROS, mainly super oxide (Hoek et al. 2002). Because ethanol metabolism by ADH and ALDH occurs primarily in the liver, any adverse effects associated with ethanol metabolism by these enzymes and associated ROS production pri marily would affect that organ. In contrast, CYP2E1, which also oxidizes ethanol, particularly following chronic alcohol intake, is found in many tissues in addition to the liver, including the brain, heart, lungs, and certain white blood cells (i.e., neu trophils and macrophages). Accordingly, metabolic consequences of CYP2E mediated ethanol oxidation would affect numerous tissues. Harmful effects asso ciated with CYP2E1-mediated ethanol metabolism primarily are related to the production of ROS, mainly superoxide and hydroxyl radicals. This ROS pro duction contributes to alcohol-induced damage to a variety of tissues not only by causing oxidative stress but also by enhancing apoptosis triggered by vari ous stimuli. In the liver, CYP2E mediated ethanol metabolism generates oxidative stress that leads to DNA dam age and may thereby play an important role in alcohol-related development of liver cancer (Bradford et al. 2005).
Effects on Fetal Development
Oxidative stress plays an important role in ethanol-induced damage to the developing fetus (Cohen-Kerem and Koren 2003). Low levels of CYP2E are found in prenatal brain (Brezezinki et al. 1999), suggesting that CYP2E derived ROS could play a role in the development of alcohol-related birth defects, including fetal alcohol syn drome (FAS). Moreover, ROS pro duced during CYP2E1-mediated ethanol metabolism would likely be particularly harmful because the fetal brain shows only low levels of antioxi dant enzyme activity compared with adult brain (Henderson et al. 1999). Researchers have studied whether administration of antioxidants, such as N -acetyl cysteine, SAMe, folic acid,
and vitamin C, could improve cell sur vival during fetal ethanol exposure; however, these studies have yielded mixed results. Nonoxidative metabolism of ethanol by phospholipase D also has been impli cated in alcohol-related birth defects. As mentioned earlier, phospholipase D normally is a critical component in cel lular signal transduction processes, and the presence of ethanol interferes with these pathways. Alcohol-induced inhi bition of these signaling processes dur ing fetal development impairs the pro liferation of certain brain cells (i.e., astroglial cells) and may contribute to the reduced brain size (i.e., microen cephaly) found in most children diag nosed with FAS (Costa et al. 2004).
Impairment of Other Metabolic Processes Chronic ethanol consumption and alcohol metabolism also may influence various other metabolic pathways, thereby contributing to metabolic dis orders frequently found in alcoholics, such as fatty liver and excessive levels of lipids in the blood (i.e., hyperlipi demia), accumulation of lactic acid in the body fluids (i.e., lactic acidosis), excessive production of chemical com pounds known as ketones in the body (i.e., ketosis), and elevated levels of uric acid in the blood (i.e., hyperuricemia). The liver is most commonly affected by alcohol-induced damage. The first stage of liver damage following chronic alcohol consumption is the appearance of fatty liver, which is followed by inflammation, apoptosis, fibrosis, and finally cirrhosis. The development of fatty liver is induced by the shift in the redox state of the hepatocytes that results from ethanol metabolism by ADH. This shift in the redox state favors the accumulation of fatty acids, rather than their oxidation. In addition to these metabolic effects, chronic ethanol consumption contributes to the development of fatty liver by influenc ing the activities of several proteins that help regulate fatty acid synthesis and oxidation (Nagy 2004). Other metabolic derangements asso ciated with ethanol metabolism result
from the fact that ADH and ALDH metabolize not only ethanol but also other compounds. For example, ADH and ALDH oxidize retinol (i.e., vita min A 1 ) to retinal and, subsequently, retinoic acid, which plays an important role in growth and differentiation. In the presence of ethanol, ADH and ALDH may be occupied with ethanol metabolism and retinol metabolism may be inhibited. These interactions may have serious implications for fetal development, stem cell differentiation, maintenance of differentiated tissue function, and the normal structure and function of stellate cells in the liver (Crabb et al. 2001). Chronic alcohol consumption also is associated with disturbances in the metabolism of sulfur-containing amino acids, leading to increased levels of the amino acids glutamate, aspartate, and homocysteine in alcoholic patients. These increases may have serious adverse effects. For example, homocys teine increases and modulates certain nerve signaling processes, particularly during alcohol withdrawal, and increases in homocysteine levels may possibly contribute to the alcoholism-associated tissue shrinkage (i.e., atrophy) observed in brain tissue (Bleich et al. 2004).
Cancer Risk and Medication Interactions Chronic alcohol consumption greatly enhances the risk of developing cancer of the esophagus and oral cavity (Seitz et al. 2004) and plays a major role in the development of liver cancer (Stickel et al. 2002). Several mechanisms have been identified that contribute to ethanol-associated tumor development, some of which are related to alcohol metabolism. For example, the acetalde hyde generated during alcohol metabolism promotes cancer develop ment, as does induction of CYP2E leading to ROS formation (Pöschl and Seitz 2004). Induction of CYP2E1 following heavy alcohol consumption also has other potentially harmful consequences:
- Enhanced alcohol metabolism by CYP2E1 contributes to alcoholics’
252 Alcohol Research & Health
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