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Home , Acetaldehyde, ADH1B, ADH5, ADH6, ADH7, Alcohol

Overview: How Is Metabolized by the Body?

Samir Zakhari, Ph.D.

Alcohol is eliminated from the body by various metabolic mechanisms. The primary involved are (ALDH), (ADH), P450 (CYP2E1), and . Variations in the for these enzymes have been found to influence alcohol consumption, alcohol-related damage, and . The consequences of alcohol include deficits (i.e., hypoxia) in the ; 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 (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 state); tissue damage; fetal damage; impairment of other metabolic processes; ; and interactions. Several issues related to alcohol metabolism require further research. KEY WORDS: -to­ metabolism; alcohol dehydrogenase (ADH); (ALDH); acetaldehyde; ; 2E1 (CYP2E1); catalase; reactive oxygen species (ROS); alcohol concentration (BAC); liver; ; brain; fetal alcohol effects; genetics and heredity; ethnic group; hypoxia

The alcohol elimination rate varies state of liver cells. Chronic alcohol con- he effects of alcohol (i.e., ethanol) widely (i.e., three-fold) among individ- sumption and alcohol metabolism are on various tissues depend on its uals and is influenced by factors such as strongly linked to several pathological concentration in the blood T chronic alcohol consumption, diet, age, consequences and tissue damage. (blood alcohol concentration [BAC]) , and time of day (Bennion and Understanding the balance of alcohol’s over time. BAC is determined by how Li 1976; Kopun and Propping 1977). removal and the accumulation of poten­ quickly alcohol is absorbed, distributed, The consequent deleterious effects tially damaging metabolic byproducts, metabolized, and excreted. After alco­ caused by equivalent amounts of alco- as well as how alcohol metabolism affects hol is swallowed, it is absorbed primar­ hol also vary among individuals. Even other metabolic pathways, is essential ily from the into the after moderate alcohol consumption, for appreciating both the short-term that collect blood from the stom- BAC can be considerable (0.046 to and long-term effects of the body’s ach and bowels and from the portal 0.092 gram-percent [g%]; in the 10- to response to alcohol intake. , which leads to the liver. From 20-millimolar1 [mM] range). Alcohol there it is carried to the liver, where it is readily diffuses across membranes and exposed to enzymes and metabolized. distributes through all cells and tissues, Alcohol Metabolism The rate of the rise of BAC is influ­ and at these concentrations, it can acutely enced by how quickly alcohol is emp- Although the liver is the main tied from the stomach and the extent affect cell function by interacting with certain and cell membranes. responsible for metabolizing ingested of metabolism during this first pass alcohol, stomach (i.e., gastric) ADH through the stomach and liver (i.e., As explained in this article, alcohol metabolism also results in the genera­ has been reported to contribute to FPM. first-pass metabolism [FPM]). The relative contribution of the stom­ BAC is influenced by environmen- tion of acetaldehyde, a highly reactive and toxic byproduct that may contribute ach and the liver to FPM, however, is tal factors (such as the rate of alcohol controversial. Thus, whereas FPM is drinking, the presence of food in the to tissue damage, the formation of stomach, and the type of alcoholic bev­ damaging molecules known as reactive erage) and genetic factors (variations in oxygen species (ROS), and a change in the reduction–oxidation (or redox) SAMIR ZAKHARI, PH.D., is director, the principal alcohol-metabolizing Division of Metabolism and Health Effects, enzymes alcohol dehydrogenase [ADH] 1A millimole represents a concentration of 1/1,000 (one National Institute on and and aldehyde dehydrogenase [ALDH2]). thousandth) molecular weight per liter (mol/L). , Bethesda, Maryland.

Vol. 29, No. 4, 2006 245 attributed predominantly to the stom­ remove (through pathways Table 1, ADH constitutes a complex ach (Lim et al. 1993; Baraona 2000), involving ADH, cytochrome P450, and family, and, in , five other previous studies (Lee et al. 2006) catalase enzymes), and nonoxidative classes have been categorized based on stress the role of the liver. pathways. their kinetic and structural properties. ADH3, which is present in the liver At high concentrations, alcohol is elim­ and stomach, metabolizes alcohol inated at a high rate because of the poorly at physiological BACs (i.e., 0.23 Oxidative Pathways presence of enzyme systems with high 2 g% BAC [or <50 mM]) in the liver but activity levels (Km), such as class II may play an important role in FPM in As shown in Figure 1, ADH, cytochrome ADH, β3-ADH (encoded by ADH4 the stomach, because gastric alcohol P450 2E1 (CYP2E1), and catalase all and ADH1B genes, respectively) and concentrations can reach molar range contribute to oxidative metabolism of CYP2E1 (Bosron et al. 1993). This during alcohol consumption (Baraona et ethanol. oxidation process involves an interme­ al. 2001; Lee et al. 2003). However, diate carrier of electrons, Crabb (1997) pointed out the insuffi­ ADH. The major pathway of oxidative dinucleotide (NAD+), which is ciency of gastric ADH to account for metabolism of ethanol in the liver reduced by two electrons to form FPM, so this remains unresolved. involves ADH (present in the fluid of NADH. As a result, Alcohol also is metabolized in nonliver the cell [i.e., cytosol]), an enzyme with generates a highly reduced cytosolic (i.e., extrahepatic) tissues that do not many different variants (i.e., ). environment in liver cells (i.e., hepato­ contain ADH, such as the brain, by the Metabolism of ethanol with ADH pro­ cytes). In other words, these reactions enzymes cytochrome P450 and catalase duces acetaldehyde, a highly reactive 2 (see below). In general, alcohol meta­ and toxic byproduct that may con­ Km is a measurement used to describe the activity of an enzyme. It describes the concentration of the substance bolism is achieved by both oxidative tribute to tissue damage and, possibly, upon which an enzyme acts that permits half the maxi­ pathways, which either add oxygen or the addictive process. As shown in mal rate of reaction.

Figure 1 Oxidative pathways of alcohol metabolism. The enzymes alcohol dehydrogenase (ADH), cytochrome P450 2E1 (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 , requires (H2O2) 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.

246 Alcohol Research & Health Alcohol Metabolism and the Body

odeoxyguanosine. Formation of Table 1 Human Alcohol Dehydrogenase (ADH) Isozymes adducts in impairs protein secretion, which has been pro­ Class Nomenclature Protein Km Vmax Tissue posed to play a role in enlargement of New Former mM min-1 the liver (i.e., ). I ADH1A ADH1 ααα 4.0 30 Liver ADH1B*1 ADH2*1 β 1 0.05 4 Liver, Acetate. Acetate, produced from the ADH1B*2 ADH2*2 β 2 0.9 350 oxidation of acetaldehyde, is oxidized ADH1B*3 ADH2*3 β 40.0 300 3 to dioxide (CO2). Most of the ADH1C*1 ADH3*1 γ 1 1.0 90 Liver, Stomach acetate resulting from alcohol meta­ ADH1C*2 ADH3*2 γ 2 0.6 40 bolism escapes the liver to the blood II ADH4 ADH4 π 30.0 20 Liver, Cornea III ADH5 ADH5 χ >1,000 100 Most Tissues and is eventually metabolized to CO2 IV ADH7 ADH7 σ(µ) 30.0 1,800 Stomach in , skeletal muscle, and brain V ADH6 ADH6 ? ? Liver, Stomach cells. Acetate is not an inert product; it increases blood flow into the liver NOTE: The ADH1B and ADH1C genes have several variants with differing levels of enzymatic activity. Km is a measurement used to describe the activity of an enzyme. It describes the concentration of the substance upon and depresses the central nervous sys­

which an enzyme acts that permits half the maximal rate of reaction. It is expressed in units of concentration. Vmax tem, as well as affects various metabolic is a measure of how fast an enzyme can act. It is expressed in units of product formed per time. processes (Israel et al. 1994). Acetate also is metabolized to acetyl CoA, which leave the liver cells in a state that is par­ alcohol consumption by has been is involved in and ticularly vulnerable to damage from the shown to result in increased H2O2 pro­ in the mitochondria of byproducts of ethanol metabolism, duction in pericentral regions of the peripheral and brain tissues. It is hypoth­ such as free radicals and acetaldehyde. liver and increased catalase activity esized that upon chronic alcohol intake (Misra et al. 1992). The role of the brain starts using acetate rather than Cytochrome P450. The cytochrome CYP2E1 and catalase in alcohol as a source of energy. P450 isozymes, including CYP2E1, metabolism in the brain are described 1A2, and 3A4, which are present pre­ in detail elsewhere (Zimatkin and dominantly in the microsomes, or vesi­ Deitrich 1997). Nonoxidative Pathways cles, of a network of membranes within the cell known as the endoplasmic reticu­ The nonoxidative metabolism of alcohol Products of Oxidative Metabolism is minimal, but its products may have lum, also contribute to alcohol oxida­ of Alcohol tion in the liver. CYP2E1 is induced by pathological and diagnostic relevance. chronic alcohol consumption and Acetaldehyde and acetate, produced from Alcohol is nonoxidatively metabolized assumes an important role in metabo­ the oxidative metabolism of alcohol, by at least two pathways. One leads to lizing ethanol to acetaldehyde at ele­ contribute to cell and tissue damage in the formation of molecules called fatty vated ethanol concentrations (Km = 8 to various ways. ethyl (FAEEs) from the reac­ 10 mM, compared with 0.2 to 2.0 mM tion of alcohol with fatty ––weak for hepatic ADH). In addition, CYP2E1­ Acetaldehyde. Acetaldehyde, produced organic acids that play functional roles dependent ethanol oxidation may occur by alcohol oxidation through any of in human cells. The other nonoxidative in other tissues, such as the brain, where the mechanisms outlined above, is pathway results in the formation of a ADH activity is low. It also produces rapidly metabolized to acetate, mainly type of (i.e., lipid) con­ ROS, including hydroxyethyl, superox­ by ALDH2 (in cell bodies called mito­ taining (i.e, phospholipid) ide anion, and hydroxyl radicals, which chondria), to form acetate and NADH. known as phosphatidyl ethanol (see increase the risk of tissue damage. NADH then is oxidized by a series of Figure 2). FAEEs are detectable in chemical reactions in the mitochondria serum and other tissues after alcohol Catalase. Another enzyme, catalase, (i.e., the mitochondrial electron trans­ ingestion and persist long after alcohol located in cell bodies called peroxi­ port chain, or respiratory chain). is eliminated. The role of FAEEs in somes, is capable of oxidizing ethanol Acetaldehyde has the capacity to bind alcohol-induced tissue damage remains in vitro in the presence of a hydrogen to proteins such as enzymes, microso­ to be further evaluated. peroxide (H2O2)-generating system, mal proteins, and microtubules. It also The second nonoxidative pathway such as the enzyme complex NADPH forms adducts with the brain signaling requires the enzyme or the enzyme oxi­ chemical (i.e., ) (PLD) (Laposata 1999), which breaks dase. Quantitatively, however, this is to form salsolinol, which down phospholipids (primarily phos­ considered a minor pathway of alcohol may contribute to alcohol dependence, phatidylcholine) to generate phosphatidic oxidation, except in the fasted state and with DNA to form carcinogenic acid (PA). This pathway is a critical (Handler and Thurman 1990). Chronic DNA adducts such as 1,N2-propan­ component in cellular communication.

Vol. 29, No. 4, 2006 247 PLD has a high Km for ethanol, and sumption. These variations have been (see Agarwal 2001), and these different the enzymatic reaction does occur pre­ attributed to both genetic and environ­ genes are associated with varying levels dominantly at high circulating alcohol mental factors, gender, drinking pattern, of enzymatic activity. The ADH1B concentrations. The product of this fasting or fed states, and chronic alcohol variations (i.e., alleles) occur at differ­ reaction, phosphatidyl ethanol, is poorly consumption. The following section will ent frequencies in different populations. metabolized and may accumulate to focus on the relevant genetic factors. For example, the ADH1B*1 form is detectable levels following chronic con­ found predominantly in Caucasian and sumption of large amounts of alcohol, Genetic Variation in ADH Black populations, whereas ADH1B*2 but its effects on the cell remain to be and ALDH frequency is higher in Chinese and established. However, the formation of Japanese populations and in 25 percent phosphatidyl ethanol occurs at the Class I ADH and ALDH2 play a of people with Jewish ancestry. expense of the normal function of PLD, central role in alcohol metabolism. ADH1C*1 and ADH1C*2 appear with namely to produce PA, resulting in Variations in the genes encoding roughly equal frequency in Caucasian inhibited PA formation and disruption ADH and ALDH produce alcohol- populations (Li 2000). People of Jewish of cell signaling. and acetaldehyde-metabolizing descent carrying the ADH1B*2 allele Oxidative and nonoxidative pathways enzymes that vary in activity. This show only marginally (<15 percent) of alcohol metabolism are interrelated. genetic variability influences a person’s higher alcohol elimination rates com­ Inhibition of ethanol oxidation by com­ susceptibility to developing alcoholism pared with people with ADH1B*1 pounds that inhibit ADH, CYP2E1, and alcohol-related tissue damage. (Neumark et al. 2001). Also, African and catalase results in an increase in the Americans (Thomasson et al. 1995) nonoxidative metabolism of alcohol and ADH. The ADH gene family encodes and Native Americans (Wall et al. increased production of FAEEs in the enzymes that metabolize various sub­ 1996) with the ADH1B*3 allele liver and (Werner et al. 2002). stances, including ethanol. The activity metabolize alcohol at a faster rate than of these enzymes varies across different those with ADH1B*1. organs (see Table 1). When ethanol is Genetic Aspects of present, the metabolism of the other Alcohol Metabolism ALDH. Several isozymes of ALDH substances that ADH acts on may be have been identified, but only the cyto­ inhibited, which may contribute to solic ALDH1 and the mitochondrial Variations in the rate of alcohol absorp­ ethanol-induced tissue damage. ALDH2 metabolize acetaldehyde. tion, distribution, and elimination con­ As shown in Table 1, genetic varia­ tribute significantly to clinical conditions tion (i.e., polymorphism) occurs at the There is one significant genetic poly­ observed after chronic alcohol con­ ADH1B and ADH1C gene locations 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, Tissue injury and Japanese populations (Shen et al. FAEE synthase 1997) and shows virtually no acetalde­ hyde metabolizing activity in vitro. People who have one (i.e., heterozy­ gous) or especially two (i.e., homozy­ ethyl (FAEE) gous) copies of the ALDH2*2 allele Ethanol show increased acetaldehyde levels after Phosphatidyl ethanol alcohol consumption (Luu et al. 1995; Wall et al. 1997) and therefore experi­ ence negative physiological responses to alcohol. PLD Interferes with Because polymorphisms of ADH PLD-dependent signaling? and ALDH2 play an important role in determining peak blood acetaldehyde levels and voluntary ethanol consump­ Figure 2 Ethanol is nonoxidatively metabolized by two pathways. A reaction tion (Quintanilla et al. 2005), they also catalyzed by the enzyme fatty acid ethyl ester (FAEE) synthase leads influence vulnerability to alcohol depen­ to the formation of molecules known as FAEEs. A reaction with the dence. A fast ADH or a slow ALDH enzyme phospholipase D (PLD) results in the formation of a phospho­ are expected to elevate acetaldehyde lipid known as phosphatidyl ethanol. levels and thus reduce alcohol drinking. These polymorphisms and their signifi-

248 Alcohol Research & Health Alcohol Metabolism and the Body

cance are discussed in the article in this ported that study participants with a and Xi 1989). If the hepatocytes that issue by Quertemont and Didone. polymorphism of CYP2E1 (CYP2E1 are located close to the supplying ADH and ALDH activity RsaI) were more likely than others to oxygen-rich blood to the liver take up also influences the prevalence of alcohol- be lifetime abstainers at age 68 or older. more than their normal share of oxy­ induced tissue damage. Alcoholic cir­ Burim and colleagues (2004) found an gen, however, not enough oxygen may rhosis is reduced more than 70 percent in association between having the m2/m2 be left in the blood to adequately supply populations carrying the ALDH2*2 CYP1A1 gene and alcoholic liver cir­ other liver regions with oxygen. Indeed, allele (Chao et al. 1994; Nagata et al. rhosis and the Val/Val GSTP1 (gluta­ strong evidence suggests that alcohol 2002). In a review of studies, Yokoyama thione S-) gene and chronic consumption results in significant hypoxia and Omori (2003) reported a positive . in those hepatocytes that are located correlation between genetic polymor­ close to the vein where the cleansed phisms for low-activity ADH and blood exits the liver (i.e., in the perive­ ALDH and esophageal and head and Consequences of Alcohol nous hepatocytes) (Arteel et al. 1996). neck . In another study (Hines Metabolism The perivenous hepatocytes also are et al. 2001), moderate drinkers who are the first ones to show evidence of dam­ homozygous for the slow-oxidizing The different pathways of ethanol age from chronic alcohol consumption ADH1C*2 allele, and therefore who are metabolism described above have (Ishak et al. 1991), indicating the expected to at higher levels than numerous detrimental consequences potential harmful consequences of those with the ADH1C*1 allele, showed that contribute to the tissue damage hypoxia induced by ethanol metabolism. a substantially decreased risk of heart and seen in alcoholic patients. In addition to directly increasing attack (i.e., myocardial infarction). The These consequences include oxygen hepatocytes’ oxygen use as described authors (Hines et al. 2001, p. 549) only deficits (i.e., hypoxia) in the liver; inter­ above, ethanol indirectly increases the differentiated drinkers versus nondrinkers action between alcohol metabolism cells’ oxygen use by activating Kupffer at one drink per day (“Men who con­ byproducts and other cell components, cells in the liver. When these cells sumed at least one drink per day and resulting in the formation of harmful become activated, they release various were homozygous for the gamma2 compounds (i.e., adducts); formation stimulatory molecules. One of these allele had the greatest reduction in risk of highly reactive oxygen-containing molecules is E2, which [relative risk 0.14]”). molecules (i.e., reactive oxygen species stimulates the metabolic activity of Interestingly, elevated acetaldehyde [ROS]) that can damage other cell hepatocytes—that is, it induces them levels induced by ALDH inhibitors components; and changes in the ratio to break down and synthesize many were shown to protect against alcohol- of NADH to NAD+ (i.e., the cell’s essential molecules through a variety induced in experimental redox state [see Glossary]). These con­ of chemical reactions that also require (Lindros et al. 1999) and to sequences and the way they contribute oxygen. As a result, alcohol-induced reduce the release of a signaling to tissue damage and will be activation also contributes molecule (i.e., cytokine) called tumor discussed in the following sections. to the onset of hypoxia. necrosis factor alpha (TNF-α) from Kupffer cells (Nakamura et al. 2004). Hypoxia Adduct Formation This finding is quite contradictory to the belief that acetaldehyde plays a role As mentioned earlier, the main path­ Ethanol metabolism by ADH and in liver damage. In a meta-analysis of way of alcohol metabolism, which CYP2E1 produce reactive molecules, most studies in the literature, Zintzaras involves ADH and ALDH, results in such as acetaldehyde and ROS, that and colleagues (2005) found that nei­ the generation of NADH. The NADH can interact with protein building ther ADH nor ALDH alleles were sig­ then is oxidized by a series of chemical blocks (i.e., amino acids) and other nificantly associated with liver . reactions in the mitochondria (i.e., the molecules in the cell to form both sta­ mitochondrial electron transport sys­ ble and unstable adducts (see Table 2). Genetic Variation in CYP2E1 tem, or respiratory chain), eventually resulting in the transfer of electrons to Acetaldehyde Adducts. Acetaldehyde Although several CYP2E1 polymor­ molecular oxygen (O2), which then interacts with certain amino acids in phisms have been identified, only a few binds protons (H+) to generate proteins (e.g., , , and studies were undertaken to determine (H2O). To have enough oxygen avail­ some of a group of amino acids called the effect on alcohol metabolism and able to accept the electrons, the hepato­ aromatic amino acids). However, not tissue damage. In one study (Ueno et cytes must take up more oxygen than all amino acids in all proteins are equally al. 1996), the presence of the rare c2 normal from the blood. Consistent likely to interact with acetaldehyde, allele was associated with higher alco­ with this assumption, studies have and certain proteins seem to be partic­ hol metabolism in Japanese alcoholics shown that ethanol metabolism tends ularly susceptible to forming adducts but only at high BACs (0.25 g/dL). to increase the hepatocytes’ oxygen with acetaldehyde. These include the Raimondi and colleagues (2004) re­ uptake from the blood (Tsukamoto following (Tuma and Casey 2003):

Vol. 29, No. 4, 2006 249 which can form adducts with proteins Table 2 Ethanol Metabolites and Adducts Generated During Ethanol Metabolism (Worrall and Thiele 2001). In addi­ tion, acetaldehyde and MDA together Metabolites and Adducts Source can react with proteins to generate a stable MDA–acetaldehyde–protein Acetaldehyde Ethanol metabolism adduct (MAA) (Tuma et al. 1996; Tuma Malondialdehyde (MDA) Nonenzymatic lipid peroxidation of unsaturated 2002). All of these adducts can induce fatty acids, breakdown of in immune responses (e.g., the formation of ) (Tuma and Casey 2003). 4-hydroxynonenal (HNE) Lipid peroxidation of long-chain polyunsaturated Moreover, MAA adducts can induce fatty acids inflammatory processes in certain types Malondialdehyde-Acetaldehyde Hybrid adducts with malondialdehyde and of liver cells (i.e., stellate cells and Adduct (MAA) acetaldehyde endothelial cells) (Tuma 2002). These Hydroxyethyl (HER) Ethanol oxidation in the presence of and other findings indicate a link between MDA, HNE, and MAA adducts and subsequent development of (Tuma and Casey 2003). • Proteins found in the membranes bind to the adducts and induce the surrounding the red blood cells (i.e., to destroy the hepato­ erythrocytes). cytes containing these adducts. This Formation of ROS and Decrease in process is known as immune-mediated Antioxidants • that consist of a pro­ or -dependent ROS, including superoxide (O •–), tein and a fat component and which cell-mediated cytotoxicity (ADCC). 2 hydrogen peroxide (H2O2), hypochlo­ are associated with the risk of heart Antibodies directed against other rite (OCl–), and hydroxyl (•OH) disease. acetaldehyde–protein adducts also have radicals, are naturally generated by been found in the blood of alcoholics many reactions in multiple regions of • Tubulin, a protein found in cell (Lin et al. 1990; Worrall et al. 1990). the cell. ROS act by “stealing” hydro­ structures called microtubules that Adducts formed by the interaction gen from other molecules, are essential for cell division and of acetaldehyde with erythrocyte thereby converting those molecules protein transport within cells. membranes have been detected in the into highly reactive free radicals. Alter­ erythrocytes of alcohol abusers. These natively, ROS can combine with stable • , which is crucial for adducts may be associated with ethanol- molecules to form free radicals. Through oxygen transport by the erythrocytes. induced macrocytosis, a condition both of these mechanisms, ROS play characterized by unusually large numbers an important role in cancer develop­ • , which is a protein found of enlarged erythrocytes in the blood ment (i.e., ), atheroscler­ in the blood. (Niemela and Parkkila 2004). Macrocytosis osis, diabetes, , aging, and is a marker for alcohol abuse. other harmful processes. To prevent the • Collagen, the major protein in con­ Finally, acetaldehyde can form damage these highly reactive compounds nective tissue. adducts by interacting with compounds can cause, numerous defense systems known as biogenic ,3 which have evolved in the body involving • Cytochrome enzymes, such as include, among others, neurotransmit­ compounds called antioxidants, which CYP2E1, which play a role in the ters such as and dopamine. can interact with ROS and convert metabolism of ethanol and many These adducts may have pharmacologi­ them into harmless molecules. Under other substances. cal effects on the . (For normal conditions, a balance between more information on adduct formation ROS and antioxidants exists in the Acetaldehyde–lysine adducts were and other detrimental effects of acetalde­ cells. When this balance is disturbed detected in the plasma membrane hyde, see the article by Quertemont and an excess of ROS is present, a state of hepatocytes from alcohol-fed rats and Didone, p. 258). known as oxidative stress results. (Barry et al. 1987). These adducts can In most cells, the vast majority of indirectly contribute to liver damage ROS Formation. As mentioned earlier, ROS are generated in association with because the body recognizes them as ethanol metabolism by CYP2E1 and the mitochondrial electron transport “foreign” and therefore generates NADH oxidation by the electron trans­ system. In addition, ROS are produced immune molecules (i.e., antibodies) port chain generate ROS that results in by CYP2E1 and by activated Kupffer against them. The presence of such lipid peroxidation. This process results antibodies has been demonstrated fol­ in the formation of compounds known 3Biogenic amines are organic compounds formed during lowing chronic alcohol consumption as malondialdehyde (MDA) and 4­ biochemical processes in plants and animals that carry a (Israel et al. 1986). The antibodies hydroxy-2-nonenal (HNE), both of as a central molecule.

250 Alcohol Research & Health Alcohol Metabolism and the Body

cells in the liver. Both acute and chronic dria can escape the mitochondria into (i.e., expression) of certain genes. For alcohol consumption can increase ROS the cytosol. The release of a compound example, studies of the effects of production and lead to oxidative stress called cytochrome c into the cytosol, reduced food intake (i.e., caloric restric­ though a variety of pathways, includ­ for example, induces a chain of bio­ tion) on found that ing, but not limited to, the following chemical reactions that ultimately under conditions of caloric restriction, (Wu and Cederbaum 2003): causes a certain type of cell death (i.e., NAD+ levels may act as a sensor that cell suicide, or apoptosis). Moreover, regulates the activity of certain genes • Changes in the cells’ redox state peroxidation of molecules in the mito­ (Imai et al. 2000). Activation of those (i.e., in the ratio of NADH to chondrial membranes alters the distri­ genes, in turn, has been shown to NAD+) as a result of ethanol bution of electrical charges across the extend the lifespan in a wide variety of metabolism by ADH and ALDH, membrane, which results in reduced organisms and to reduce the incidence which results in production of more levels of ATP in the cell and promotes of age-related diseases, such as diabetes, NADH. another type of cell death called necro­ cancer, immune deficiencies, and car­ sis. Both apoptosis and necrosis con­ diovascular disorders (Bordone and • Acetaldehyde formation. tribute to alcohol-related liver damage. Guarente 2005). Changes in the To prevent or ameliorate the harm­ NADH/NAD+ ratio resulting from • Induction of CYP2E1 at high alco­ ful effects caused by ROS, researchers ethanol metabolism might likewise hol levels. have studied the effects of antioxidant influence gene expression. administration. These studies found • Hypoxia related to alcohol that replenishment of by metabolism. administering the glutathione precursor Tissue Damage, Metabolic S-adenosyl-L-methionine (SAMe) or Derangements, and Disease • Alcohol-induced damage to the the use of other antioxidants attenu­ Associated With Ethanol mitochondria. ated alcohol-induced liver damage (see Metabolism Wu and Cederbaum 2003). • Activation of Kupffer cells. Changes in NADH/NAD+ Levels Tissue Damage • Reduction of the levels of certain and Gene Activation antioxidants (e.g., mitochondrial The direct actions of alcohol (e.g., dis­ and cytosolic glutathione). NADH and NAD+ are involved in ordering of membrane components many important cellular reactions, and and effects on signaling proteins) and • Formation of the 1-hydroxyethyl the levels of the two compounds in the the indirect effects resulting from radical mentioned above. cell, as well as their ratio, in many cases ethanol metabolism described in the determines the rate at which these cel­ previous sections act in concert to induce The relative contributions of these lular reactions can proceed. The ratio tissue damage. In fact, ethanol meta­ factors to the increase in ROS levels is of NADH to NAD+ frequently fluctu­ bolism often is considered to be the unknown (Bailey 2003). Regardless of ates in response to changes in metabo­ predominant factor causing alcohol- how they were generated, however, lism. Ethanol oxidation, as mentioned associated tissue damage, particularly increases in ROS levels have numerous before, results in a significant increase through the generation of ROS and detrimental effects. For example, ROS in the hepatic NADH/NAD+ ratio in oxidative stress in the tissues. ROS are stimulate the release of TNF-α from both the cytosol and mitochondria generated during ethanol and acetalde­ Kupffer cells. This cytokine plays an (Cunningham et al. 1986; Bailey and hyde oxidation both by ADH/ALDH important role in activating inflamma­ Cunningham 1998). In the cytosol, the and by CYP2E1. The rate of ethanol tory reactions that can contribute to conversion of ethanol to acetaldehyde and acetaldehyde oxidation by ADH tissue damage and scar tissue formation by ADH generates NADH, the reduc­ and ALDH is determined by the rate (i.e., ) in the liver. In addition, ing equivalents of which are then trans­ with which the NADH generated can ROS can interact with , proteins, ported into the mitochondria by pass through the mitochondrial elec­ and DNA in a process called peroxida­ molecules known as the malate–aspar­ tron transport system. Because the tion, which can have harmful conse­ tate shuttle. In the mitochondria, most mitochondrial electron transport sys­ quences. For example, as described in of the NADH is produced by ALDH. tem requires oxygen and generates the previous section, lipid peroxidation Through both of these pathways, ATP, the rate of NADH oxidation leads to the generation of MDA and ethanol oxidation vastly increases the depends both on the cell’s oxygen sup­ HNE. Peroxidation of mitochondrial availability of NADH to the electron ply and on its demand for ATP. If membranes alters the membranes’ transport chain in the mitochondria. either of these two factors is limited, properties (e.g., membrane permeabil­ In addition to its many effects on electron transport activity is reduced. ity) so that certain molecules that nor­ biochemical reactions, the NADH/ This has two effects: First, ethanol and mally are contained in the mitochon­ NAD+ ratio also may affect the activity acetaldehyde are inefficiently metabo-

Vol. 29, No. 4, 2006 251 lized, and, second, electrons passing and C, could improve cell sur­ from the fact that ADH and ALDH through the mitochondrial electron vival during fetal ethanol exposure; metabolize not only ethanol but also transport chain are “diverted” into however, these studies have yielded other compounds. For example, ADH forming harmful ROS, mainly super­ mixed results. and ALDH oxidize (i.e., vita­ oxide (Hoek et al. 2002). Because Nonoxidative metabolism of ethanol min A1) to and, subsequently, ethanol metabolism by ADH and by phospholipase D also has been impli­ , which plays an important ALDH occurs primarily in the liver, cated in alcohol-related birth defects. role in growth and differentiation. In any adverse effects associated with As mentioned earlier, phospholipase D the presence of ethanol, ADH and ethanol metabolism by these enzymes normally is a critical component in cel­ ALDH may be occupied with ethanol and associated ROS production pri­ lular processes, and metabolism and retinol metabolism marily would affect that organ. the presence of ethanol interferes with may be inhibited. These interactions In contrast, CYP2E1, which also these pathways. Alcohol-induced inhi­ may have serious implications for fetal oxidizes ethanol, particularly following bition of these signaling processes dur­ development, differentiation, chronic alcohol intake, is found in ing fetal development impairs the pro­ maintenance of differentiated tissue many tissues in addition to the liver, liferation of certain brain cells (i.e., function, and the normal structure and including the brain, heart, , and astroglial cells) and may contribute to function of stellate cells in the liver certain white blood cells (i.e., neu­ the reduced brain size (i.e., microen­ (Crabb et al. 2001). trophils and ). Accordingly, cephaly) found in most children diag­ Chronic alcohol consumption also metabolic consequences of CYP2E1­ nosed with FAS (Costa et al. 2004). is associated with disturbances in the mediated ethanol oxidation would affect metabolism of -containing amino numerous tissues. Harmful effects asso­ Impairment of Other Metabolic acids, leading to increased levels of the ciated with CYP2E1-mediated ethanol Processes amino acids glutamate, aspartate, and metabolism primarily are related to the homocysteine in alcoholic patients. production of ROS, mainly superoxide Chronic ethanol consumption and These increases may have serious and hydroxyl radicals. This ROS pro­ alcohol metabolism also may influence adverse effects. For example, homocys­ duction contributes to alcohol-induced various other metabolic pathways, teine increases and modulates certain damage to a variety of tissues not only thereby contributing to metabolic dis­ signaling processes, particularly by causing oxidative stress but also by orders frequently found in alcoholics, during alcohol withdrawal, and increases enhancing apoptosis triggered by vari­ such as fatty liver and excessive levels of in homocysteine levels may possibly ous stimuli. In the liver, CYP2E1­ lipids in the blood (i.e., hyperlipi­ contribute to the alcoholism-associated mediated ethanol metabolism generates demia), accumulation of in tissue shrinkage (i.e., atrophy) observed oxidative stress that leads to DNA dam­ the body fluids (i.e., ), in brain tissue (Bleich et al. 2004). age and may thereby play an important excessive production of chemical com­ role in alcohol-related development of pounds known as in the body Cancer Risk and Medication (Bradford et al. 2005). (i.e., ), and elevated levels of uric Interactions acid in the blood (i.e., ). Effects on Fetal Development The liver is most commonly affected Chronic alcohol consumption greatly by alcohol-induced damage. The first enhances the risk of developing cancer Oxidative stress plays an important role stage of liver damage following chronic of the and oral cavity (Seitz in ethanol-induced damage to the alcohol consumption is the appearance et al. 2004) and plays a major role in developing (Cohen-Kerem and of fatty liver, which is followed by the development of liver cancer (Stickel Koren 2003). Low levels of CYP2E1 inflammation, apoptosis, fibrosis, and et al. 2002). Several mechanisms have are found in prenatal brain (Brezezinki finally cirrhosis. The development of been identified that contribute to et al. 1999), suggesting that CYP2E1­ fatty liver is induced by the shift in the ethanol-associated tumor development, derived ROS could play a role in the redox state of the hepatocytes that some of which are related to alcohol development of alcohol-related birth results from ethanol metabolism by metabolism. For example, the acetalde­ defects, including fetal alcohol syn­ ADH. This shift in the redox state hyde generated during alcohol drome (FAS). Moreover, ROS pro­ favors the accumulation of fatty acids, metabolism promotes cancer develop­ duced during CYP2E1-mediated rather than their oxidation. In addition ment, as does induction of CYP2E1 ethanol metabolism would likely be to these metabolic effects, chronic leading to ROS formation (Pöschl and particularly harmful because the fetal ethanol consumption contributes to the Seitz 2004). brain shows only low levels of antioxi­ development of fatty liver by influenc­ Induction of CYP2E1 following dant enzyme activity compared with ing the activities of several proteins that heavy alcohol consumption also has adult brain (Henderson et al. 1999). help regulate and other potentially harmful consequences: Researchers have studied whether oxidation (Nagy 2004). administration of antioxidants, such as Other metabolic derangements asso­ • Enhanced alcohol metabolism by N-acetyl cysteine, SAMe, folic acid, ciated with ethanol metabolism result CYP2E1 contributes to alcoholics’

252 Alcohol Research & Health Alcohol Metabolism and the Body

BLEICH, S.; DEGNER, D.; SPERLING, W.; ET AL. metabolic tolerance for ethanol, the interactions between ethanol Homocysteine as a in chronic alco­ thereby promoting further alcohol metabolism, diabetes, and obesity? holism. Progress in Neuro- & consumption. Answers to these and other questions Biological Psychiatry 28:453–464, 2004. PMID will further elucidate the mechanisms 15093951 • CYP2E1 metabolizes not only underlying ethanol’s metabolism and BORDONE, L., AND GUARRENTE, L. Calorie restriction, ethanol but also numerous other their regulation, as well as the effects SIRT1 and metabolism: Understanding longevity. compounds, including many medi­ that alcohol metabolism and its Nature 6:298–305, 2005. PMID: 15768047 cations. Induction of CYP2E1 also byproducts have on all tissues and BOSRON, W.F.; EHRIG, T.; AND LI, T.K. Genetic affects the metabolism of these med­ organs throughout the body. In addi­ factors in alcohol metabolism and alcoholism. Seminars ications, potentially making them tion, a deeper understanding of these in Liver Disease 13:126–135, 1993. PMID: 8337601 less effective. metabo­ processes will allow researchers to BRADFORD, B.U.; KONO, H.; ISAYAMA, F.; ET AL. lized by CYP2E1 include, among design intervention strategies that may Cytochrome P450 CYP2E1, but not nicotinamide others, (which is pre­ ameliorate the harmful effects of alco­ adenine dinucleotide phosphate oxidase, is required scribed for the treatment of hyper­ for ethanol-induced oxidative DNA damage in hol and its metabolites. ■ rodent liver. 41:336–344, 2005. PMID: tension and disturbances of the 15660387 heart rhythm), the pain medication acetaminophen, the blood thinner BURIM, R.V.; CANALLE, R.; MARTINELLI ADE, L.; Financial Disclosure AND TAKAHASHI, C.S. Polymorphisms in glutathione , and the . 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