17 Alcohol and the Liver:

Metabolism of Alcohol and Its Role in Hepatic and Extrahepatic Diseases

Abstract
Dr. Charles S. Lieber has conducted clinical and experimental studies for more than four decades (three at Mount Sinai and the Bronx VA Medical Centers) with emphasis on liver, nutrition and GI pathophysiology. His major contributions include elucidation of the pathogenesis of alcoholic liver disease, by demonstrating the toxic role of alcohol and describing associated metabolic disorders. This was achieved through judicious clinical studies and newly developed rodent and primate models with the administration of ethanol in liquid diets. The mechanisms of various pathological and metabolic effects of ethanol were clarified, including hyperlipemia (with the rise in HDL), hyperuricemia, the role of acetaldehyde toxicity and alcohol-induced oxidative stress. The latter, including glutathione depletion, was corrected by S-adenosyl-1-methionine given to alcohol-fed baboons; the compound is now being used successfully for the treatment of patients with alcoholic liver disease in Europe. Alcoholic cirrhosis was produced for the first time in nonhuman primates and shown to be fully prevented by polyenylphosphatidylcholine, which is now being tested in a multicenter clinical trial. Lieber also discovered a new (microsomal) pathway of ethanol metabolism, responsible for the tolerance to ethanol and for several clinically important toxic interactions with other drugs (e.g., acetaminophen), anesthetics, industrial solvents, carcinogens, as well as retinol and -carotene, with narrowing of their therapeutic window. His work defined the role of the stomach in ethanol metabolism, description of corresponding gender differences, cloning (for the first time) of the gene for sigma ADH (a newly recognized gastric alcohol dehydrogenase isozyme) with its chromosomal localization, and the discovery of the effects of commonly used medications (e.g., H2 blockers and aspirin) on the activities of the enzyme and on blood alcohol levels in social drinkers. Lieber was among the first to use antibiotics for the elimination of gastric bacterial urease and its ammonia production in man, thereby alleviating chronic gastritis and hypoacidity, with attenuation of hepatic encephalopathy in cirrhotics. He promoted early detection and treatment of heavy drinkers before their social or medical disintegration, by defining precirrhotic lesions and markers of alcohol consumption. Conclusions: The research of Dr. Lieber and his group has yielded a better understanding of the pathogenesis of common hepatic, gastric and nutritional disorders, with elucidation and prevention of serious toxic alcohol-drug interactions and the development of methods for early recognition and more effective approaches to prevent and treat liver and gastrointestinal diseases. Key Words: Ethanol, liver, cirrhosis, drugs, nutrition.

A. Alcohol and Nutrition E T H A N O L I S A P S Y C H O A C T I V E D R U G , but, besides its pharmacologic action, it has a substantial energy value (7.1 kcal/g). In the heavy drinker, alcohol represents, on the average, 50% of the total dietary energy intake. As a consequence, alcohol displaces many normal nutrients of the diet, resulting in primary malnutrition and associated symptomatology (Fig. 1). Alcohol also
Section of Liver Disease and Nutrition, Alcohol Research and Treatment Center, Bronx VA Medical Center, Bronx, NY. Address correspondence to Charles S. Lieber, M.D., Bronx VA Medical Center (151-2), 130 West Kingsbridge Road, Bronx, NY 10468.
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impairs the activation and utilization of nutrients, and secondary malnutrition may result from either maldigestion or malabsorption caused by gastrointestinal complications associated with alcoholism. Originally, it was believed that liver disease in the alcoholic was due exclusively to malnutrition. This dogma was primarily based on the experiments of Best and Hartroft, who had observed that in rats given alcohol as part of their liquid diet, no liver damage resulted when the diet was adequate. The first stage of liver disease, namely fatty liver, only developed when the diet was deficient. From their experiments, Best et al. (1) concluded that there is no more evidence of a specific toxic effect of pure ethyl alcohol upon
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B. Alcohol Metabolism and Associated Toxicity Alcohol is oxidized primarily in the liver and the main pathway involves alcohol dehydrogenase. 1. Metabolic Disorders Associated with Alcohol Oxidation by Alcohol Dehydrogenase a. Hepatic effects The oxidation of ethanol via the alcohol dehydrogenase pathway results in the production of acetaldehyde with loss of H. Nicotinamide adenine dinucleotide (NAD) is reduced to NADH. The large amounts of reducing equivalents generated overwhelm the hepatocytes ability to maintain redox homeostasis, and it was shown that a number of metabolic disorders ensue (Fig. 2), including hyperuricemia (6) and hyperlipemia (2), with a rise in HDL (7) popularized more recently in conjunction with some apparently beneficial effects of moderate drinking on coronary arteries. It was also found that the increased NADH opposes lipid oxidation and promotes fatty acid synthesis with, as a net result, hepatic fat accumulation (8). The perivenular exaggeration of this redox change (because of the relative perivenular hypoxia) was found to be responsible for the exacerbation of the alcohol-induced injury (including steatosis) in the perivenular zone of the hepatic lobule (9). The respective roles of the amount of dietary fat (10) and dietary deficiencies (11) were elucidated. An associated metabolic disorder, namely ketoacidosis, was discovered and defined (12). In addition to the raised NADH, microsomal induction (vide infra) was incriminated through increased activity of enzymes involved in lipogenesis (13, 14) which was found to be associated with enhanced production of low and very low density lipoproteins (LDL and VLDL) (15). LDL and VLDL, in addition to alterations in cholesterol turnover (16), were shown to play a role in the alcohol-induced hyperlipemia (17 19). The latter was observed to involve the high density lipoproteins (HDL). Their increase was described by Baraona and Lieber (7), and has gained much attention in recent years. Ethanol was also found to affect the lipids, the microviscosity (20) and the structure of plasma membranes, as demonstrated by scanning electron microscopy (21). Thus, the hypothesis that the NADH generated by alcohol dehydrogenase (ADH)-mediated ethanol oxidation may play a major role in alcohol-induced disorders (22) was shown indeed to explain a vast array of associated metabolic abnormalities, including the steatosis (Fig. 2).

Fig. 1. Interaction of direct toxicity of ethanol on liver and gut with malnutrition secondary to dietary deficiencies, maldigestion, and malabsorption, as well as impaired hepatic activation or increased degradation of nutrients (154).

liver cells than there is for one due to sugar. Lieber et al. confirmed these experiments but added the observation that under those conditions, blood alcohol levels were negligible. Indeed, rats have a natural aversion for alcohol that was overcome by giving alcohol in totally liquid diets (2). This diet also allowed perfect pair feeding of controls and, using such a diet, it was established for the first time that alcohol, even in the absence of nutritional deficiencies, can cause the first stage of alcoholic liver disease, namely a fatty liver, a finding confirmed in human volunteers (2, 3). The question still remained of the pathogenesis of the more severe stages of alcoholic liver disease, culminating in cirrhosis, which is responsible for the high rate of mortality in the heavy drinker. This issue was addressed by extending the liquid diet technique to an experimental animal more closely related to man, namely nonhuman primates (4). The latter studies were conducted after Dr. Lieber and his team had moved from Harvard and Cor nell to the Bronx Veterans Affairs (VA) Medical Center and the newly created Mount Sinai School of Medicine in 1968. There, it was shown for the first time that alcohol can cause cirrhosis of the liver, even in the absence of nutritional deficiencies (4, 5). This realization had profound consequences on the preventive as well as therapeutic approaches to the medical disorders of alcoholism. The major therapeutic efforts shifted from the mere correction of nutritional deficiencies to the moderation of alcohol consumption and the development of new therapeutic modalities by a better understanding of the mechanism of hepatotoxicity. The latter was investigated by a systematic study of the biochemical pathways through which the body rids itself of the alcohol.

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Fig. 2. Hepatic, nutritional and metabolic abnormalities after ethanol abuse. Malnutrition, whether primary or secondary, can be differentiated from metabolic changes or direct toxicity, resulting partly from redox changes, or effects secondary to microsomal induction, including increased acetaldehyde production (155).

b. Gastric effects 1. Gastric ethanol metabolism and interactions with other drugs Chronic ethanol consumption was found to produce a significant decrease in gastric alcohol dehydrogenase (ADH) activities (23), associated with greater bioavailability (lesser first pass metabolism) of ethanol (23, 24). Significant ethanol metabolism was also observed in cultured rat (25) and human (26) gastric cells. Women were found to have a lower gastric ethanol metabolism than men, which explains, at least in part, their greater susceptibility to the effects of ethanol (27). Commonly used drugs, e.g., aspirin (28) and H2 receptor antagonists, e.g., cimetidine (29), were discovered to inhibit gastric ADH activity and to enhance the bioavailability of ethanol, with a resulting increase in blood ethanol levels (30). This effect was shown to be particularly important for social drinkers who commonly take several small drinks, with a cumulative effect on blood alcohol levels, strikingly exaggerated by various drugs (Fig. 3), either because of an inhibition of gastric ADH (vide supra) and/or an acceleration of gastric emptying (31). At least three different forms of ADH were observed in the human stomach, with either high or low Kms for ethanol (32), including a newly recognized gastric isozyme, now called class IV or sigma ADH. A deficiency of this gastric ADH was uncovered in Asians (33), and the lower

Fig. 3. Effects of cimetidine (400 mg twice a day for 7 days) on average blood levels after oral consumption of ethanol in nine subjects. Four small doses of ethanol (150 mg/kg) were imbibed at 45-min intervals, before and after administration of cimetidine. The effect of cimetidine on repeated drinking was significant (p < 0.01 by two-way analysis of variance for repeated measures). (Modified from ref. 156).

ADH activity was found to be associated with a lesser first pass metabolism of ethanol (34), in keeping with a predominant role for ADH in human first pass metabolism. The full length cDNA of sigma ADH was determined and the complete amino acid sequence deduced (35). The corresponding ADH 7 gene in Caucasian and Japanese subjects was compared (36), including the upstream structure and the organ distribution of its expression (37) with, for the first time, molecular cloning and chromosomal localization of the gene (38). These studies not only established

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the role of gastric ADH in ethanol metabolism, but they also delineated corresponding differences at a molecular level and opened a new approach to explain differences in the handling of ethanol and possibly of other dietary xenobiotics, such as gastric carcinogens. 2. Gastritis in the alcoholic The product of ethanol metabolism is acetaldehyde, a toxic compound (vide infra) which may contribute to the chronic gastritis which is common in the alcoholic. An additional pathogenic factor is Helicobacter pylori infection (HP). Indeed it was found that this chronic gastritis generally resolves with the eradication of the microbe (39). The role of the gastric microbial flora in converting urea into NH3 was first recognized by the successful elimination of gastric NH 3 using antibiotics in man (40, 41). These studies were completed at Mount Sinai (42). Adverse effects of NH3 included hypoacidity and gastritis, especially in the alcoholic (41). Gastric NH3 was shown to correlate with the severity of gastritis (39), and its measurement is now the basis for an accurate, yet simple, method for the detection of HP (43). The infection has its most striking impact in patients with uremia (40, 41) and in those with cirrhosis whose encephalopathy was improved with the antibiotic therapy (44). Other gastrointestinal effects of ethanol that were elucidated comprised significant intestinal lesions in the rat (45), confirmed in man (46). These alterations included B12 malabsorption (47) and decrease of intestinal lactase (46). 2. Microsomal Ethanol Oxidizing System (MEOS) a. Ethanol metabolism A toxicological breakthrough was achieved with the discovery of a microsomal ethanol oxidizing system and its interactions with xenobiotics (48, 49). This second pathway for alcohol metabolism was separate from that of alcohol dehydrogenase and catalase (49, 50) and characterized (51) and reconstituted by a semi-purified preparation of cytochrome P-450 (52). The role of the microsomes in ethanol metabolism and its increase after chronic ethanol consumption was demonstrated in rats (53), nonhuman primates (54, 55), acatalasemic mice (56), and deermice lacking alcohol dehydrogenase (57 62). It was quantitated using, in part, deuterium isotope effects (61). An ethanol-inducible form of cytochrome P-450 was discovered (52) and was subsequently purified by various groups from the livers of different species, including rats (63) and humans (64); it is now called 2E1. Unlike ADH,

MEOS was found to be strikingly inducible by chronic ethanol consumption, with its key component, namely 2E1, increased 4- to 10-fold in liver biopsies of recently drinking subjects (65), with a corresponding rise in mRNA in hamsters (66), rats (67) and man (68). P4502E1 induction was demonstrated with normal, as well as low-fat diets (69). It was shown in hepatocytes and in nonparenchymal cells of the liver (70), and also in extrahepatic tissues (71). b. Other microsomal effects Microsomal induction was found to have an impact on sex hormones in normal men (72), and to enhance fatty acid -oxidation (73). Induction of 2E1 contributes to the tolerance that develops to ethanol in the alcoholic and other drugs that are microsomal substrates. The tolerance of the alcoholic to various psychoactive drugs had generally been attributed to central nervous system adaptation, but metabolic adaptation now had to be considered, because the clearance rate of many drugs from the blood was found to be enhanced in alcoholics (74). Indeed, controlled studies have shown that chronic administration of pure ethanol with nondeficient diets either to rats or man (under metabolic ward conditions) results in a striking increase in the rate of blood clearance of ethanol (75), meprobamate and pentobarbital (74) as well as other drugs. Contrasting the effect of chronic ethanol consumption, which results in microsomal induction and tolerance to a number of drugs, the presence of ethanol may slow down disposition of some drugs and enhance their pharmacologic effects by competing for some common component(s) of the microsomal degradation process. This was shown for meprobamate (76), acetaminophen (77, 78) as well as methadone (79). c. Activation of hepatotoxins One of the most important consequences of the discovery of this new microsomal pathway of ethanol metabolism was the realization that the ethanol-inducible cytochrome P4502E1 not only catalyzes ethanol oxidation, but is also capable of activating various other compounds to highly toxic metabolites. This pertains to analgesics, such as acetaminophen (80), anesthetics (81), hepatotoxins (82), industrial solvents (83), as well as carcinogens (e.g., nitrosodimethylamine [NDMA]) (84). Activation of the latter was achieved at concentrations significantly lower than those required after the administration of other inducers (84), in part because the ethanolinducible P4502E1, including the human variety (64), has a high affinity for NDMA. Increased activation of carcinogens was also demonstrated

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in the alimentary tract and the lungs (85). Thus, this inducible microsomal ethanol oxidizing system explains not only the metabolic tolerance to ethanol that develops in the heavy drinker, but also the concomitant increased vulnerability to ubiquitous xenobiotics. Furthermore, the proliferation of the endoplasmic reticulum (86) associated with P4502E1 induction is also accompanied by enhanced activity of other cytochrome P-450s, resulting in accelerated metabolism and tolerance to other drugs, as well as increased degradation of retinol and its hepatic depletion. d. Interactions with retinoids and carotenoids Liver microsomes were also found to harbor hitherto unrecognized pathways for retinol metabolism (87, 88) which were found to play a role in the homeostatic control of hepatic vitamin A levels (89). Using purified cytochrome P-450 isozymes, including the human P4502C8 (90), retinol (87, 90) and retinoic acid (90, 91), metabolizing systems were reconstituted; chronic ethanol or drug administration was shown to result in increased microsomal degradation of retinoic acid (92) and retinol (93). This provided a possible mechanism for the striking hepatic vitamin A depletion which was discovered to result from chronic ethanol consumption in rats (94), nonhuman primates (94), and man (95) (Fig. 4). This hepatic vitamin A depletion was associated with striking lysosomal lesions (96). Potentiation of the deleterious effects of vitamin A depletion

by ethanol was also found in other tissues, including a profound loss of the ciliated epithelium in the lining of the respiratory tract and the exacerbation of squamous metaplasia, a precancerous lesion (97). Hepatic depletion of vitamin A was also demonstrated after administration of other drugs (98); the combination of ethanol with drugs or food additives (such as butylated hydroxytoluene) resulted in a striking potentiation of the depletion, with almost all of the vitamin A disappearing from the liver (99). Thus, vitamin A requirements had to be revised for the large segment of our population that chronically abuses ethanol and/or other drugs. The practical limits of vitamin A supplementation, however, were delineated by the demonstration that vitamin A toxicity can be markedly exacerbated by chronic ethanol consumption, with development of mitochondrial injury (100), necrosis and fibrosis (101). Indeed, amounts of ethanol and vitamin A which, by themselves, did not produce fibrosis, when combined, resulted in necrosis and fibrosis in the liver (101), with development of severe mitochondrial injury (100). Furthermore, it was discovered that alcohol interferes with the clearance of carotene, possibly by impairing its conversion to vitamin A, resulting in enhanced hepatic and blood levels in baboons (102) and also in man (103), with associated potentiation of hepatotoxicity (102) possibly due, in part, to the beadlets used as carrier for -carotene (104). In addition, carotenoids were found to undergo significant biliary excretion in man (105) and are therefore affected by liver pathology. The recognition of a narrowed therapeutic window for vitamin A and -carotene in the alcoholic has prompted a redefinition of the optimal conditions for their use in nutritional repletion and therapy. C. Acetaldehyde Toxicity and Mitochondrial Impairment Ethanol oxidation, whether by the ADH or the microsomal pathway, results in acetaldehyde, which may cause ubiquitous damage, including in the mitochondria. Indeed, the ethanol-induced ultrastructural lesions of the mitochondria (86) were found to be associated with functional abnormalities, including decreased oxidation of fatty acids (106) and acetaldehyde (107, 108). The latter, together with the increased production by the induced microsomes (109), explains the elevated blood level of acetaldehyde observed in alcoholics (110). Using improved analytical methods (111), the high acetaldehyde levels were found to be reversible upon alcohol withdrawal

Fig. 4. Hepatic vitamin A levels in subjects with normal livers and various stages of alcoholic liver injury. Figures below the graph denote P values (95).

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(112), and exaggerated by pregnancy and lactation (113). The human placenta was shown to be capable both of transferring acetaldehyde from the mother to the fetus and of converting ethanol to acetaldehyde (114), which may thus play a role in the pathogenesis of the fetal alcohol syndrome, the most common preventable cause of congenital abnormalities. Administration of ethanol, particularly at high levels and in animals fed alcohol chronically, was accompanied by a 10-fold increase in splanchnic acetaldehyde release in the hepatic vein (115), associated with a striking leakage of the mitochondrial enzyme glutamic dehydrogenase into the hepatic venous blood. There was also an inappropriately low oxygen utilization by the liver. The flow-independent O2 extraction (VO2) was measured by reflectance spectroscopy with a probe placed on the liver surface through a peritoneoscope: VO2 significantly decreased after the high ethanol dose in the alcohol-treated baboons (115). This impaired O2 utilization was associated with a marked shift in the mitochondrial redox level (measured by the -hydroxybutyrate / acetoacetate ratio). A vicious cycle was thus recognized, with chronic ethanol consumption inducing increased acetaldehyde formation leading to mitochondrial toxicity, including an associated decreased capacity of the mitochondria to oxidize acetaldehyde. As a consequence, acetaldehyde rises even further, and perpetuates and aggravates the toxicity. The morphologic (116) and functional (117) impairment of the mitochondria after chronic ethanol consumption was accompanied by a significant decrease in cytochrome oxidase activity associated with the depletion of mitochondrial phosphatidylcholine, whereas restoration of cytochrome oxidative activity was achieved by replenishment of the phosphatidylcholine in vitro (117). This observation was one of the factors that led to the supplementation of phosphatidylcholine in vivo (using delinoleoylphosphatidylcholine), which resulted in the discovery of its spectacular beneficial effects, including the prevention of liver fibrosis and cirrhosis (vide infra). The uncoupling of oxidation with phosphorylation associated with mitochondrial impairment, together with the net loss of chemical energy that accompanies the operation of the induced microsomes explained, at least in part, the startling observation that alcohol calories do not fully count and why many alcoholics do not maintain an adequate body weight despite a large caloric intake (118). One mechanism for the hepatotoxicity of acetaldehyde is its high chemical reactivity and

formation of adducts with various proteins. Indeed, it was discovered that acetaldehyde binds to microsomal proteins (119) and forms adducts in vivo with P4502E1 (120), collagen (121 122), as well as VLDL and LDL (123). Acetaldehyde adducts also elicit an immune response with increased circulating antibodies in alcoholics (124). The appearance of antibodies against acetaldehyde-protein adducts was found to reflect the severity of liver disease, both in alcoholics and non-alcoholics (125). Furthermore, even in non-alcoholic liver disease, hepatic acetaldehyde was found to be increased to a potentially toxic level (126). Moreover, acetaldehyde toxicity was shown to interfere with the repair of alkylated nucleo-proteins; human and rat O6 methylguanine transferase was inhibited in vitro by minute concentrations of acetaldehyde (as low as 0.01M) (127). Acetaldehyde binding was also shown to impair microtubule polymerization and hepatic protein secretion (128, 129) which, together with an increase in constituent proteins (130), resulted in protein accumulation and hepatocyte swelling, thereby explaining the ballooning of the hepatocyte and the hepatomegaly, two characteristic features of alcohol-induced liver injury. Acetaldehyde also contributes to depletion of glutathione and its potentiation of lipid peroxidation (131), verified in human liver biopsies (132). These effects were found to be attenuated by Sadenosyl-L-methionine (133), which has now been introduced in Europe for the treatment of liver disease. The oxidative stress was exacerbated by a low vitamin E diet, and ethanol was found to aggravate hepatic vitamin E depletion, in part by promoting conversion of tocopherol to tocopheryl-quinone (134), probably by free radical reaction. Allopurinol partially prevented the ethanol-induced lipid peroxidation (135), most likely through inhibition of purine degradation (enhanced by ethanol) and the associated free radical generation. D. Fibrosis and Cirrhosis of the Liver: Pathogenesis and Prevention Traditionally, fibrosis and cirrhosis were viewed as a scarring response to the necrosis and inflammation associated with liver injury, most clearly demonstrated in alcoholic hepatitis. However, the observation that chronic alcohol administration (under controlled dietary conditions) stimulated fibrogenesis (136) and produced cirrhosis in the baboon (4) without an obvious stage of alcoholic hepatitis (137) but with evidence for increased collagen production, including enhanced type I procollagen mRNA (138),

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raised the hypothesis of a more direct effect of alcohol on fibrogenesis. Indeed, in baboons fed alcohol (139) as well as in man (140), perivenular fibrosis was identified as a precirrhotic lesion and shown to be useful for the early detection of subjects prone to rapidly develop cirrhosis, even in the absence of alcoholic hepatitis (141) (Fig. 5). Scanning electron microscopy also revealed significant changes of the endothelial fenestrations of the liver sinusoids (142), a finding of obvious implications for the exchange of nutrients and metabolites between the hepatocytes and the blood. Efforts were then directed to define the cell(s) involved. Myofibroblasts were identified in normal liver (139) and were discovered to proliferate after chronic alcohol consumption (139, 140). Furthermore, stellate cells (also called lipocytes or fat-storing cells) were found to be transformed or activated to transitional myofibroblast-like cells (143), associated with active fibrogenesis. Lipocytes and myofibroblasts were isolated from the liver and cultured, and acetaldehyde was shown to stimulate collagen production in vitro (144, 145), with an associated increase in mRNA for collagen (146). The acetaldehydeinduced increase in collagen accumulation was prevented by polyunsaturated phosphatidylcholine (PPC) extracted from soybeans (147) and by its main phosphatidylcholine species, namely dilinoleophosphatidylcholine (DLPC) (148), selected because of its high bioavailability. Several modes of action were elucidated: increased collagen breakdown (148), a significant decrease in the number of lipocytes activated to myofibroblast-like cells (148, 149), correction of the ethanol-induced depletion in phosphatidylcholine (148), as well as an attenuation of some of the associated enzyme deficiencies, including that of phosphatidylethanolamine methyltransferase (150). More recently, PPC was also found

to prevent alcohol-induced steatosis and hyperlipemia (151) and to exert an unexpected but potent antioxidant effect (152) of possible relevance to the fibrosis, since the latter is known to be stimulated by products of lipid peroxidation. Furthermore, PPC prevented or attenuated nonalcoholic cirrhosis produced by either CCl 4 or heterologous albumin in the rat and accelerated the regression of preexisting cirrhosis (153). PPC is now being tested in man. Acknowledgments The original studies reviewed here were supported by NIH grants AA05934, AA11115, AA07275, AA03508, the Department of Veteran Affairs, and the Kingsbridge Research Foundation. The skillful preparation of the manuscript by Ms. Shawn Dickerson is gratefully acknowledged
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Fig. 5. Progression of fibrosis in alcoholics without hepatitis followed up to eight years after initial biopsy. The presence of perivenular fibrosis on the initial biopsy specimen was found to be a harbinger of rapid development of fibrosis to more severe stages, including cirrhosis (141).

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32. Hernandez-Munoz R, Caballeria J, Baraona E, et al. Human gastric alcohol dehydrogenase: Its inhibition by H2-receptor antagonists, and its effect on the bioavailability of ethanol. Alcohol Clin Exp Res 1990; 14:946 950. 33. Baraona E, Yokoyama A, Ishii H, et al. Lack of alcohol dehydrogenase isoenzyme activities in the stomach of Japanese subjects. Life Sci 1991; 49:1929 1934. 34. Dohmen K, Baraona E, Ishibashi H, et al. Ethnic differences in gastric -alcohol dehydrogenase activity and ethanol firstpass metabolism. Alcohol Clin Exp Res 1996; 20:1569 1576. 35. Yokoyama H, Baraona E, Lieber CS. Molecular cloning of human class IV alcohol dehydrogenase. Biochem Biophys Res Commun 1994; 203:219 224. 36. Yokoyama H, Baraona E, Lieber CS. Comparison of the ADH7 gene structure in Caucasian and Japanese subjects. Biochem Biophys Res Commun 1995; 212:875 878. 37. Yokoyama H, Baraona E, Lieber CS. Upstream structure of human ADH7 gene and the organ distribution of its expression. Biochem Biophys Res Commun 1995; 216:216 222. 38. Yokoyama H, Baraona E, Lieber CS. Molecular cloning and chromosomal localization of ADH7 gene encoding human class IV ADH. Genomics 1996; 31:243 245. 39. Uppal R, Lateef SK, Korsten MA, et al. Chronic alcoholic gastritis: Roles of ethanol and Helicobacter pylori. Arch Intern Med 1991; 151:760 764. 40. Lieber CS, Lefvre A. Effect of oxytetracycline on acidity, ammonia and urea in gastric juice in normal and uremic subjects. C R Seances Soc Biol Fil 1957; 151:1038 1042. 41. Lieber CS, Lefvre A. Ammonia as source of gastric hypoacidity in patients with uremia. J Clin Invest 1959; 38:1271 1277. 42. Meyers S, Lieber CS. Reduction of gastric ammonia by ampicillin in normal and azotemic subjects. Gastroenterology 1976; 70:244 247. 43. Mokuolu AO, Sigal SH, Lieber CS. Gastric juice urease activity as a diagnostic test for Helicobacter pylori infection. Am J Gastroenterol 1997; 92:644 648. 44. Lieber CS, Lefvre A. Ammonia and intermediary metabolism in hepatic coma: Value of the determination of blood ammonia in the diagnosis and management of cirrhosis. Acta Clin Belg 1958; 13:328 357. 45. Baraona E, Pirola RC, Lieber CS. Small intestinal damage and changes in cell population produced by ethanol ingestion in the rat. Gastroenterology 1974; 66:226 234. 46. Perlow W, Baraona E, Lieber CS. Symptomatic intestinal disaccharidase deficiency in alcoholics. Gastroenterology 1977; 72:680 684. 47. Lindenbaum J, Lieber CS. Alcohol induced malabsorption of vitamin B12 in man. Nature 1969; 224:806. 48. Lieber CS, DeCarli LM. Ethanol oxidation by hepatic microsomes: Adaptive increase after ethanol feeding. Science 1968; 162:917 918. 49. Lieber CS, DeCarli LM. Hepatic microsomal ethanol oxidizing system: In vitro characteristics and adaptive properties in vivo. J Biol Chem 1970; 245:2505 2512. 50. Teschke R, Hasumura Y, Lieber CS. Hepatic microsomal ethanol oxidizing system: Solubilization, isolation and characterization. Arch Biochem Biophys 1974; 163:404 415. 51. Teschke R, Hasumura Y, Lieber CS. Hepatic microsomal alcohol oxidizing system: Affinity for methanol, ethanol, propanol and butanol. J Biol Chem 1975; 250:7397 7404.

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52. Ohnishi K, Lieber CS. Reconstitution of the microsomal ethanol oxidizing system (MEOS): Qualitative and quantitative changes of cytochrome P-450 after chronic ethanol consumption. J Biol Chem 1977; 252:7124 7131. 53. Lieber CS, DeCarli LM. The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo. J Pharmacol Exp Ther 1972; 181:279 287. 54. Pikkarainen PH, Lieber CS. Concentration dependency of ethanol elimination rates in baboons: Effect of chronic alcohol consumption. Alcohol Clin Exp Res 1980; 4:40 43. 55. Nomura F, Pikkarainen PH, Jauhonen P, et al. The effect of ethanol administration on the metabolism of ethanol in baboons. J Pharmacol Exp Ther 1983; 227(1):78 83. 56. Teschke R, Hasumura Y, Lieber CS. Hepatic microsomal alcohol oxidizing system in normal and acatalasemic mice: Its dissociation from the peroxidatic activity of catalase-H2O2. Mol Pharmacol 1975; 11:841 849. 57. Shigeta Y, Nomura F, Iida S, et al. Ethanol metabolism in vivo by the microsomal ethanol oxidizing system in deermice lacking alcohol dehydrogenase (ADH). Biochem Pharmacol 1984; 33:807 814. 58. Takagi T, Alderman J, Gellert J, Lieber CS. Assessment of the role of non-ADH ethanol oxidation in vivo and in hepatocytes from deermice. Biochem Pharmacol 1986; 35:3601 3606. 59. Kato S, Alderman J, Lieber CS. Respective roles of the microsomal ethanol oxidizing system (MEOS) and catalase in ethanol metabolism by deermice lacking alcohol dehydrogenase. Arch Biochem Biophys 1987; 254:586 591. 60. Kato S, Alderman J, Lieber CS. In vivo role of the microsomal ethanol oxidizing system in ethanol metabolism by deermice lacking alcohol dehydrogenase. Biochem Pharmacol 1988; 37:2706 2708. 61. Alderman J, Takagi T, Lieber CS. Ethanol metabolizing pathways in deermice: Estimation of flux calculated from isotope effects. J Biol Chem 1987; 262:7497 7503. 62. Alderman J, Kato S, Lieber CS. The microsomal ethanol oxidizing system mediates metabolic tolerance to ethanol in deermice lacking alcohol dehydrogenase. Arch Biochem Biophys 1989; 271:33 39. 63. Ryan DE, Iida S, Wood AW, et al. Characterization of three highly purified cytochromes P-450 from hepatic microsomes of adult male rats. J Biol Chem 1984; 259:1239 1250. 64. Lasker JM, Raucy J, Kubota S, et al. Purification and characterization of human liver cytochrome P-450-ALC. Biochem Biophys Res Commun 1987; 148:232 238. 65. Tsutsumi M, Lasker JM, Shimizu M, et al. The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver. Hepatology 1989; 10:437 446. 66. Kubota S, Lasker JM, Lieber CS. Molecular regulation of ethanol inducible cytochrome P450-IIE1 in hamsters. Biochem Biophys Res Commun 1988; 150:304 310. 67. Tsutsumi M, Lasker JM, Takahashi T, Lieber CS. In vivo induction of hepatic P4502E1 by ethanol: Role of increased enzyme synthesis. Arch Biochem Biophys 1993; 304:209 218. 68. Takahashi T, Lasker JM, Rosman AS, Lieber CS. Induction of cytochrome P4502E1 in human liver by ethanol is caused by a corresponding increase in encoding messenger RNA. Hepatology 1993; 17:236 245. 69. Lieber CS, Lasker JM, DeCarli LM, et al. Role of acetone, dietary fat and total energy intake in induction of hepatic microsomal ethanol oxidizing system. J Pharmacol Exp Ther 1988; 247:791 795.

70. Koivisto T, Mishin V, Mak KM, et al. The induction of cytochrome P4502E1 by ethanol in rat Kupffer cells. Alcohol Clin Exp Res 1996; 20:207 212. 71. Shimizu M, Lasker JM, Tsutsumi M, Lieber CS. Immunohistochemical localization of ethanol-inducible P450IIE1 in the rat alimentary tract. Gastroenterology 1990; 99:1044 1053. 72. Gordon GG, Altman K, Southren AL, et al. The effect of alcohol (ethanol) administration on sex hormone metabolism in normal men. N Engl J Med 1976; 295:793 797. 73. Ma X, Baraona E, Lieber CS. Alcohol consumption enhances fatty acid -oxidation, with a greater increase in males than in females. Hepatology 1993; 18:1247 1253. 74. Misra PS, Lefvre A, Ishii H, et al. Increase of ethanol meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats. Am J Med 1971; 51:346 351. 75. Salaspuro MP, Lieber CS. Non-uniformity of blood ethanol elimination: Its exaggeration after chronic consumption. Ann Clin Res 1978; 10:294 297. 76. Rubin E, Gang H, Misra PS, Lieber CS. Inhibition of drug metabolism by acute ethanol intoxication: A hepatic microsomal mechanism. Am J Med 1970; 49:801 806. 77. Altomare E, Leo MA, Lieber CS. Interaction of acute ethanol administration with acetaminophen metabolism and toxicity in rats fed alcohol chronically. Alcohol Clin Exp Res 1984; 8:405 408. 78. Altomare E, Leo MA, Sato C, et al. Interaction of ethanol with acetaminophen metabolism in the baboon. Biochem Pharmacol 1984; 33:2207 2212. 79. Borowsky SA, Lieber CS. Interaction of methadone and ethanol metabolism. J Pharmacol Exp Ther 1978; 207:123 129. 80. Sato C, Matsuda Y, Lieber CS. Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat. Gastroenterology 1981; 80:140 148. 81. Tsutsumi R, Leo MA, Kim C, et al. Interaction of ethanol with enflurane metabolism and toxicity: Role of P450IIE1. Alcohol Clin Exp Res 1990; 14:174 179. 82. Ma X, Baraona E, Lasker JM, Lieber CS. Effects of ethanol consumption on bioactivation and hepatotoxicity of Nnitrosodimethylamine in rats. Biochem Pharmacol 1991; 42:585 591. 83. Hasumura Y, Teschke R, Lieber CS. Increased carbon tetrachloride hepatotoxicity, and its mechanism, after chronic ethanol consumption. Gastroenterology 1974; 66:415 422. 84. Garro AJ, Seitz HK, Lieber CS. Enhancement of dimethylnitrosamine metabolism and activation to a mutagen following chronic ethanol consumption. Cancer Res 1981; 41:120 124. 85. Seitz HK, Garro AJ, Lieber CS. Enhanced pulmonary and intestinal activation of procarcinogens and mutagens after chronic ethanol consumption in the rat. Eur J Clin Invest 1981; 11:33 38. 86. Lane BP, Lieber CS. Ultrastructural alterations in human hepatocytes following ingestion of ethanol with adequate diets. Am J Pathol 1966; 49:593 603 87. Leo MA, Lieber CS. New pathway for retinol metabolism in liver microsomes. J Biol Chem 1985; 260:5228 5231. 88. Leo MA, Kim C, Lieber CS. NAD+-dependent retinol dehydrogenase in liver microsomes. Arch Biochem Biophys 1987; 259:241 249. 89. Leo MA, Kim CI, Lieber CS. Role of vitamin A degradation for the control of hepatic levels in the rat. J Nutr 1989; 119:993 1000.

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90. Leo MA, Lasker JM, Raucy JL, et al. Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8. Arch Biochem Biophys 1989; 269:305 312. 91. Leo MA, Iida S, Lieber CS. Retinoic acid metabolism by a system reconstituted with cytochrome P-450. Arch Biochem Biophys 1984; 234:305 312. 92. Sato M, Lieber CS. Increased metabolism of retinoic acid after chronic ethanol consumption in rat liver microsomes. Arch Biochem Biophys 1982; 213:557 564. 93. Leo MA, Lowe N, Lieber CS. Interaction of drugs and retinol. Biochem Pharmacol 1986; 35:3949 3953. 94. Sato M, Lieber CS. Hepatic vitamin A depletion after chronic ethanol consumption in baboons and rats. J Nutr 1981; 111:2015 2023. 95. Leo MA, Lieber CS. Hepatic vitamin A depletion in alcoholic liver injury. N Engl J Med 1982; 307:597 601. 96. Leo MA, Sato M, Lieber CS. Effect of hepatic vitamin A depletion on the liver in humans and rats. Gastroenterology 1983; 84:562 572. 97. Mak KM, Leo MA, Lieber CS. Potentiation by ethanol consumption of tracheal squamous metaplasia caused by vitamin A deficiency in rats. J Natl Cancer Inst 1987; 79:1001 1010. 98. Leo MA, Lowe N, Lieber CS. Decreased hepatic vitamin A after drug administration in men and in rats. Am J Clin Nutr 1984; 40:1131 1136. 99. Leo MA, Lowe N, Lieber CS. Potentiation of ethanol-induced hepatic vitamin A depletion by phenobarbital and butylated hydroxytoluene. J Nutr 1987; 117:70 76. 100. Leo MA, Arai M, Sato M, Lieber CS. Hepatotoxicity of vitamin A and ethanol in the rat. Gastroenterology 1982; 82:194 205. 101. Leo MA, Lieber CS. Hepatic fibrosis after long term administration of ethanol and moderate vitamin A supplementation in the rat. Hepatology 1983; 3:1 11. 102. Leo MA, Kim CI, Lowe N, Lieber CS. Interaction of ethanol with -carotene: Delayed blood clearance and enhanced hepatotoxicity. Hepatology 1992; 15:883 891. 103. Ahmed S, Leo MA, Lieber CS. Interactions between alcohol and beta-carotene in patients with alcoholic liver diseases. Am J Clin Nutr 1994; 60:430 436. 104. Leo MA, Aleynik SI, Aleynik MR, Lieber CS. -carotene beadlets potentiate hepatotoxicity of alcohol. Am J Clin Nutr 1997; 66:1461 1469. 105. Leo MA, Ahmed S, Aleynik S, et al. Carotenoids and tocopherols in various hepatobiliary conditions. J Hepatol 1995; 23:550 556. 106. Matsuzaki S, Lieber CS. Increased susceptibility of hepatic mitochondria to the toxicity of acetaldehyde after chronic ethanol consumption. Biochem Biophys Res Commun 1977; 75:1059 1065. 107. Hasumura Y, Teschke R, Lieber CS. Acetaldehyde oxidation by hepatic mitochondria: Its decrease after chronic ethanol consumption. Science 1975; 189:727 729. 108. Hasumura Y, Teschke R, Lieber CS. Characteristics of acetaldehyde oxidation in rat liver mitochondria. J Biol Chem 1976; 251:4908 4913. 109. Pikkarainen PH, Gordon ER, Lebsack ME, Lieber CS. Determinants of plasma free acetaldehyde levels during the oxidation of ethanol: Effects of chronic ethanol feeding. Biochem Pharmacol 1981; 30:799 802. 110. Korsten MA, Matsuzaki S, Feinman L, Lieber CS. High blood acetaldehyde levels after ethanol administration: Differences between alcoholic and non-alcoholic subjects. N Engl J Med 1975; 292:386 389.

111. Di Padova C, Alderman J, Lieber CS. Improved methods for the measurement of acetaldehyde concentrations in plasma and red blood cells. Alcohol Clin Exp Res 1986; 10:86 89. 112. Di Padova C, Worner TM, Lieber CS. The effect of abstinence on the blood acetaldehyde response to a test dose of alcohol in alcoholics. Alcohol Clin Exp Res 1987; 11:559 561. 113. Gordon BHJ, Baraona E, Miyakawa H, et al. Exaggerated acetaldehyde response after ethanol administration during pregnancy and lactation in rats. Alcohol Clin Exp Res 1985; 9:17 22. 114. Karl PI, Gordon BHJ, Lieber CS, Fisher SE. Acetaldehyde production and transfer by the perfused human placental cotyledon. Science 1988; 242:273 275. 115. Lieber CS, Baraona E, Hernandez-Munoz R, et al. Impaired oxygen utilization: A new mechanism for the hepatotoxicity of ethanol in sub-human primates. J Clin Invest 1989; 83:1682 1690. 116. Arai M, Leo MA, Nakano M, Gordon ER, Lieber CS. Biochemical and morphological alterations of baboon hepatic mitochondria after chronic ethanol consumption. Hepatology 1984; 4:165 174. 117. Arai M, Gordon ER, Lieber CS. Decreased cytochrome oxidase activity in hepatic mitochondria after chronic ethanol consumption and the possible role of decreased cytochrome aa3 content and changes in phospholipids. Biochim Biophys Acta 1984; 797:320 327. 118. Pirola RC, Lieber CS. The energy cost of the metabolism of drugs, including ethanol. Pharmacology 1972; 7:185 196. 119. Nomura F, Lieber CS. Binding of acetaldehyde to rat liver microsomes: Enhancement after chronic alcohol consumption. Biochem Biophys Res Commun 1981; 100:131 137. 120. Behrens UH, Hoerner M, Lasker JM, Lieber CS. Formation of acetaldehyde adducts with ethanol-inducible P450IIE1 in vivo. Biochem Biophys Res Commun 1988; 154:584 590. 121. Behrens UJ, Ma X-L, Bychenok S, et al. Acetaldehyde-collagen adduct in CCl4-induced liver injury in rats. Biochem Biophys Res Commun 1990; 173:111 119. 122. Baraona E, Liu W, Ma XL, et al. Acetaldehyde-collagen adducts in N-nitrosodimethylamine-induced liver cirrhosis in rats. Life Sci 1993; 52:1249 1255. 123. Wehr H, Rodo M, Lieber CS, Baraona E. Acetaldehyde adducts and autoantibodies against VLDL and LDL in alcoholics. J Lipid Res 1993; 34:1237 1244. 124. Hoerner M, Behrens UJ, Worner T, Lieber CS. Humoral immune response to acetaldehyde adducts in alcoholic patients. Res Commun Chem Pathol Pharmacol 1986; 54:3 12. 125. Hoerner M, Behrens UJ, Worner TM, et al. The role of alcoholism and liver disease in the appearance of serum antibodies against acetaldehyde adducts. Hepatology 1988; 8:569 574. 126. Ma X, Baraona E, Hernandez-Munoz R, Lieber CS. High levels of acetaldehyde in non-alcoholic liver injury after threonine or ethanol administration. Hepatology 1989; 10:933 940. 127. Espina N, Lima V, Lieber CS, Garro AJ. In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. Carcinogenesis 1988; 9:761 766. 128. Baraona E, Leo M, Borowsky SA, Lieber CS. Alcoholic hepatomegaly: Accumulation of protein in the liver. Science 1975; 190:794 795. 129. Baraona E, Leo MA, Borowsky SA, Lieber CS. Pathogenesis of alcohol-induced accumulation of protein in the liver. J Clin Invest 1977; 60:546 554.

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130. Pignon J-P, Bailey NC, Baraona E, Lieber CS. Fatty acid-binding protein: A major contributor to the ethanol-induced increase in liver cytosolic proteins in the rat. Hepatology 1987; 7:865 871. 131. Shaw S, Jayatilleke E, Ross WA, et al. Ethanol induced lipid peroxidation: Potentiation by long-term alcohol feeding and attenuation by methionine. J Lab Clin Med 1981; 98:417 425. 132. Shaw S, Rubin KP, Lieber CS. Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease: Evidence of lipid peroxidation. Dig Dis Sci 1983; 28:585 589. 133. Lieber CS, Casini A, DeCarli LM, Kim et al. S-adenosyl-Lmethionine attenuates alcohol-induced liver injury in the baboon. Hepatology 1990; 11:165 172. 134. Kawase T, Kato S, Lieber CS. Lipid peroxidation and antioxidant defense systems in rat liver after chronic ethanol feeding. Hepatology 1989; 10:815 821. 135. Kato S, Kawase T, Alderman J, et al. Role of xanthine oxidase in ethanol-induced lipid peroxidation in rats. Gastroenterology 1990; 98:203 210. 136. Feinman L, Lieber CS. Hepatic collagen metabolism: Effect of alcohol consumption in rats and baboons. Science 1972; 176:795. 137. Popper H, Lieber CS. Histogenesis of alcoholic fibrosis and cirrhosis in the baboon. Am J Pathol 1980; 98:695 716. 138. Zern MA, Leo MA, Giambrone MA, Lieber CS. Increased type I procollagen mRNA levels and in vitro protein synthesis in the baboon model of chronic alcoholic liver disease. Gastroenterology 1985; 89:1123 1131. 139. Nakano M, Lieber CS. Ultrastructure of initial stages of perivenular fibrosis in alcohol-fed baboons. Am J Pathol 1982; 106:145 155. 140. Nakano M, Worner TM, Lieber CS. Perivenular fibrosis in alcoholic liver injury: Ultrastructure and histologic progression. Gastroenterology 1982; 83:777 785. 141. Worner TM, Lieber CS. Perivenular fibrosis as precursor lesion of cirrhosis. JAMA 1985; 254:627 630. 142. Mak KM, Lieber CS. Alterations in endothelial fenestrations in liver sinusoids of baboons fed alcohol: A scanning electron microscopic study. Hepatology 1984; 4:386 391. 143. Mak KM, Leo MA, Lieber CS. Alcoholic liver injury in baboons: Transformation of lipocytes to transitional cells. Gastroenterology 1984; 87:188 200.

144. Savolainen E-R, Leo MA, Timpl R, Lieber CS. Acetaldehyde and lactate stimulate collagen synthesis of cultured baboon liver myofibroblasts. Gastroenterology 1984; 87:777 787. 145. Moshage H, Casini A, Lieber CS. Acetaldehyde selectively stimulates collagen production in cultured rat liver fat-storing cells but not in hepatocytes. Hepatology 1990; 12:511 518. 146. Casini A, Cunningham M, Rojkind M, Lieber CS. Acetaldehyde increases procollagen type I and fibronectin gene transcription in cultured rat fat-storing cells through a protein synthesis-dependent mechanism. Hepatology 1991; 13:758 765. 147. Li J-J, Kim C-I, Leo MA, et al. Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. Hepatology 1992; 15:373 381. 148. Lieber CS, Robins SJ, Li J, et al. Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon. Gastroenterology 1994; 106:152 159. 149. Lieber CS, DeCarli LM, Mak KM, et al. Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin. Hepatology 1990; 12:1390 1398. 150. Lieber CS, Robins SJ, Leo MA. Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine. Alcohol Clin Exp Res 1994; 18:592 595. 151. Navder KP, Baraona E, Lieber CS. Polyenylphosphatidylcholine attenuates alcohol-induced fatty liver and hyperlipemia in rats. J Nutr 1997; 127:1800 1806. 152. Lieber CS, Leo MA, Aleynik SI, et al. Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon. Alcohol Clin Exp Res 1997; 21:375 379. 153. Ma X, Zhao J, Lieber CS. Polyenylphosphatidylcholine attenuates non-alcoholic hepatic fibrosis and accelerates its regression. J Hepatol 1996; 58:511 518. 154. Lieber CS. Alcohol and the liver: 1994 Update. Gastroenterology 1994; 106:1085 1105. 155. Lieber CS. Hepatic and other medical disorders of alcoholism: From pathogenesis to treatment. J Stud Alcohol 1997; 59:9 25. 156. Gupta AM, Baraona E, Lieber CS. Significant increase of blood alcohol by cimetidine after repetitive drinking of small alcohol doses. Alcohol Clin Exp Res 1995; 19:1083 1087.