Pathway Of Ethanol Metabolism Research Articles

B-316 Retrospective Data Analysis Reveals Unusual Metabolism Pattern of Ethanol in Pediatrics as Compared to Adult and Geriatric Populations

Abstract Background Ethanol is utilized in many pharmaceutical formulations and in the treatment of methanol poisoning. It is also consumed recreationally and is the most abused drug globally. About 95% of consumed ethanol is metabolized by alcohol dehydrogenase into acetaldehyde, followed by conversion of the acetaldehyde into acetic acid by acetaldehyde dehydrogenase. Less than one percent is metabolized via nonoxidative pathways, which may include: glucuronidation, sulfation, and the formation of fatty acid esters of ethanol. In neonates the glucuronidation pathway has been reported to be underdeveloped and matures with age. In this work, the patterns and concentrations of phase II nonoxidative metabolites of ethanol, ethyl glucuronide (EtG) and ethyl sulfate (EtS), were assessed in random urine collections of pediatric, adult, and geriatric patients. Methods Test results (n = 63498) from urine samples tested for EtG and EtS by quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) at our facility were utilized for this study. For both analytes, the lower limit of positivity was 100 ng/mL. The age range under consideration was 0–100 years. Data was partitioned into age groups: 0–17 years, 18–80 years and 81–100 years. The EtG and EtS concentrations across the partitions were compared. Results Across all ages, 60%–65% of patients had both EtG and EtS present in urine. Between 5%–10% had EtG present without EtS, and 25%–35% of patients had neither of the ethanol metabolites present. In all age groups there was a low positivity rate of EtS without the presence of EtG (0%–1%). All age partitions showed a similar pattern with the highest percentages of patients showing the presence of both metabolites, and the lowest percentage of patients showing the presence of EtS only. Markedly, there were no pediatric patient samples that had the sulfated metabolite present in the absence of the glucuronidated metabolite; this was statistically significantly different than this proportion in adults (Fisher’s Exact test, P = 0.025). This finding suggests greater glucuronidation activity in the pediatric population. Conclusion From the data presented in this work, EtG is more prevalent relative to EtS in urine samples of patients assessed for ethanol exposure. This work also shows that glucuronidation may be the predominant pathway for ethanol metabolism in pediatric populations. Although the level and frequency of ethanol exposure, as well as the time between exposure and sampling were unknown for the patients studied, the data offers insights into the relative distribution of EtG and EtS in random urine samples for pediatric and adult populations.

Polymorphisms in alcohol metabolizing genes ADH2 and ADH3 and susceptibility to pancreatitis in alcoholics

In both developed and developing countries, overuse of alcohol is a considered as the major cause of acute and chronic pancreatitis. Prolonged overconsumption of alcohol for 5–10 years typically precedes the initial attack of acute alcoholic pancreatitis. It is observed that only a minority (around 5%) of alcoholics develop pancreatitis. It is now established that the pancreas has the capacity to metabolize ethanol. Previous studies have shown that there are two major pathways of ethanol metabolism, oxidative and non-oxidative. Oxidative ethanol metabolism involves the conversion of ethanol to acetaldehyde, a reaction that is catalysed by aldehyde dehydrogenase (ADH) with contributions from cytochrome P450 enzyme (CYP2E1) and possibly also catalase. Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (AP). We investigated the association of polymorphisms in ADH enzymes with the alcoholic pancreatitis in North coastal Andhra Pradesh. Patients with alcoholic pancreatitis (AP; n = 100), alcoholic controls (AC; n = 100), and healthy controls (HC; n = 100) were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH2 and ADH3 was done by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism). The products were analysed by gel electrophoresis. The frequency distribution of ADH3*1/*1 genotype was significantly higher in AP group (54%) compared with AC (35%), and HC (42%), and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3*1/*1, ADH3*1/*2, and ADH3*2/*2 genotypes between AC and HC. There was no statistically significant difference between the frequency distribution of ADH2*1/*1, ADH2*1/*2, and ADH2*2/*2 genotypes in AP compared with AC and HC. This study shows that carriers of ADH3*1/*1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3*1/*2 and ADH3*2/*2.

Hepatobiliary Quiz (Answers)—15 (2015)

Hepatobiliary Quiz (Answers)—15 (2015)

Mechanisms of alcohol-induced hepatocellular carcinoma.

Chronic alcohol abuse is a major risk factor for hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. Alcohol can also function synergistically with other risk factors to cause HCC. Hence, alcohol consumption is a major factor affecting hepatic carcinogenesis in millions and the cause of a substantial public health burden. Chronic alcohol consumption interferes with several host anti-tumor mechanisms, thereby facilitating hepatocyte proliferation and tumorigenesis. This review summarizes the major mechanisms of alcohol-induced HCC. These include pathways of ethanol metabolism, alcohol-induced oxidative stress and hypomethylation of DNA, and interplay of alcohol with iron elevation, retinoid metabolism, the immune system, inflammatory pathways, and neoangiogenesis. The relevance of each pathway in affecting HCC transformation is a topic of intense investigation. Ongoing research will enhance our insight into the alcohol-induced occurrence of HCC and offer hope in developing better therapeutics.

Ethanol-induced oxidative stress: basic knowledge

After a general introduction, the main pathways of ethanol metabolism (alcohol dehydrogenase, catalase, coupling of catalase with NADPH oxidase and microsomal ethanol-oxidizing system) are shortly reviewed. The cytochrome P(450) isoform (CYP2E1) specifically involved in ethanol oxidation is discussed. The acetaldehyde metabolism and the shift of the NAD/NADH ratio in the cellular environment (reductive stress) are stressed. The toxic effects of acetaldehyde are mentioned. The ethanol-induced oxidative stress: the increased MDA formation by incubated liver preparations, the absorption of conjugated dienes in mitochondrial and microsomal lipids and the decrease in the most unsaturated fatty acids in liver cell membranes are discussed. The formation of carbon-centered (1-hydroxyethyl) and oxygen-centered (hydroxyl) radicals during the metabolism of ethanol is considered: the generation of hydroxyethyl radicals, which occurs likely during the process of univalent reduction of dioxygen, is highlighted and is carried out by ferric cytochrome P(450) oxy-complex (P(450)-Fe(3+)O(2) (.-)) formed during the reduction of heme-oxygen. The ethanol-induced lipid peroxidation has been evaluated, and it has been shown that plasma F(2)-isoprostanes are increased in ethanol toxicity.

Microwave-assisted extraction: a simpler and faster method for the determination of ethyl glucuronide in hair by gas chromatography–mass spectrometry

Alcohol is the most frequently abused "addictive substance" that causes serious social problems throughout the world; thus, alcoholism is of particular interest in clinical and forensic medicine. Alcohol biomarkers are physiological indicators of alcohol exposure or ingestion and may reflect the presence of an alcohol use disorder. The glucuronide conjugation is a minor pathway of ethanol metabolism. Ethyl glucuronide (EtG) is a marker of recent alcohol consumption that detects alcohol use reliably over a definite time period. The present paper describes a new method for the determination of EtG in hair. It is based both in the microwave-assisted extraction (MAE), to extract the analyte from hair samples, and gas chromatography-mass spectrometry (GC-MS), to identify and quantify the EtG in selected ion monitoring (SIM) mode. The method was applied to 15 hair samples from occasional alcohol users, obtaining positive results in all cases. It was fully validated, including a linear range (0.3-10 ng/mg) and the main precision parameters. In summary, the use of microwave-assisted extraction turned out to be a substantially simpler, faster, and a more sensitive procedure than any other conventional sample preparations.

Does Chronic Ethanol Intake Cause Chronic Pancreatitis?

To demonstrate the relationship between prolonged alcohol intake and chronic pancreatitis. Wistar rats were fed diet containing 25% concentration (vol/vol) of ethanol for 6 months. Cholecystokinin (CCK) was quantified by radioimmunoassay. Immunohistochemistry was used to detect alpha-smooth muscle actin, cyclooxygenase 2, and toll-like receptor 4 in rat pancreas. Western-blot was used to quantitatively determine the expression of nuclear factor kappaB and the above inflammatory markers. Pancreatic collagen content was quantified by measuring OH-proline. Superoxide dismutase was measured by colorimetric method. In contrast to the control group, there was little histological change in pancreatic tissue but obvious ultrastructural changes in acinar cells of the ethanol group. Cholecystokinin, amylase, and lipase were found reduced in the ethanol group. Chronic ethanol intake did not elicit any change in the expression of alpha-smooth muscle actin, cyclooxygenase 2, toll-like receptor 4, nuclear factor kappaB, pancreatic collagen, and superoxide dismutase. Long-term alcohol consumption did not cause chronic pancreatitis but impaired exocrine pancreatic function. The mechanism behind it could be associated with decreased output of intestinal CCK and lower concentration of pancreatic CCK. Furthermore, the nonoxidative pathway of ethanol metabolism was probably involved in it.

The Activity of Class I, II, III, and IV of Alcohol Dehydrogenase Isoenzymes and Aldehyde Dehydrogenase in Pancreatic Cancer

The pancreas can metabolize ethanol via oxidative pathway involving the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as well as the nonoxidative pathway. In this study, we compared the activity of ADH isoenzymes and ALDH in the pancreatic cancer with the activity in normal tissue. In addition, the differences between enzyme activities of drinkers and nondrinkers were compared. For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, we used the fluorometric methods. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. The samples were taken from 56 pancreatic cancer patients (22 drinkers and 34 nondrinkers) and 56 healthy subjects. The activity of class III ADH was significantly higher in cancer than in healthy tissues. Total activities of ADH and ALDH were not significantly different in cancer and normal cells. The differences between enzymes of drinkers and nondrinkers in both cancer and healthy tissue were not significant. Pancreatic cancer tissue exhibits higher activity of class III ADH isoenzyme than healthy tissue, and we consider that oxidative pathway of ethanol metabolism via ADH and ALDH does not play a role in pancreatic carcinogenesis.

Ethanol-induced oxidative stress and acetaldehyde formation in rat mammary tissue: Potential factors involved in alcohol drinking promotion of breast cancer

Recent studies from our laboratory provided evidence that part of the carcinogenic effects of ethanol consumption might be related to its in situ metabolism at cytosolic and microsomal levels, to the mutagen acetaldehyde and to hydroxyl and 1-hydroxyethyl radicals. In this work, we report on our experiments where Sprague–Dawley female rats were exposed to the standard Lieber & De Carli diet for 28 days. We observed: the induction of the (xanthineoxidoreductase mediated) cytosolic and microsomal (lipoxygenase mediated) pathways of ethanol metabolism; promotion of oxidative stress as shown by increased formation of lipid hydroperoxides; delay in the t-butylhydroperoxide induced chemiluminiscence, and a significant decrease in protein sulfhydryls. In addition, the epithelial cells showed ultrastructural alterations consisting of markedly irregular nuclei, with frequent invaginations at the level of the nuclear envelope, condensation of chromatin around the inner nuclear membrane, and marked dilatation of the nuclear pores showing filamentous material exiting to the cytoplasm. In conclusion, the presence in mammary epithelial cells of cytosolic and microsomal pathways of ethanol bioactivation to carcinogenic and to tumorigenic metabolites might play a role in alcohol promotion of breast cancer.

Zinc Supplementation Prevents Alcoholic Liver Injury in Mice through Attenuation of Oxidative Stress

Alcoholic liver disease is associated with zinc decrease in the liver. Therefore, we examined whether dietary zinc supplementation could provide protection from alcoholic liver injury. Metallothionein-knockout and wild-type 129/Sv mice were pair-fed an ethanol-containing liquid diet for 12 weeks, and the effects of zinc supplementation on ethanol-induced liver injury were analyzed. Zinc supplementation attenuated ethanol-induced hepatic zinc depletion and liver injury as measured by histopathological and ultrastructural changes, serum alanine transferase activity, and hepatic tumor necrosis factor-alpha in both metallothionein-knockout and wild-type mice, indicating a metallothionein-independent zinc protection. Zinc supplementation inhibited accumulation of reactive oxygen species, as indicated by dihydroethidium fluorescence, and the consequent oxidative damage, as assessed by immunohistochemical detection of 4-hydroxynonenal and nitrotyrosine and quantitative analysis of malondialdehyde and protein carbonyl in the liver. Zinc supplementation suppressed ethanol-elevated cytochrome P450 2E1 activity but increased the activity of alcohol dehydrogenase in the liver, without affecting the rate of blood ethanol elimination. Zinc supplementation also prevented ethanol-induced decreases in glutathione concentration and glutathione peroxidase activity and increased glutathione reductase activity in the liver. In conclusion, zinc supplementation prevents alcoholic liver injury in an metallothionein-independent manner by inhibiting the generation of reactive oxygen species (P450 2E1) and enhancing the activity of antioxidant pathways.

A kinetic model describing the pharmacokinetics of ethyl glucuronide in humans

The glucuronide conjugation is a minor pathway of ethanol metabolism. The determination of ethyl glucuronide (EG) in serum and urine has gained importance in forensic and other legal decisions. To prospectively calculate the serum concentration of this non-oxidative ethanol metabolite, the computer program developed includes a parameter fitting routine. Multiple ethanol doses can be handled. The mathematical modeling was based on the following assumptions and simplifications, respectively. A single enzyme system is responsible for ethanol conjugation at one distinct site; the distribution of EG into the systemic circulation is delayed; the elimination of EG follows first-order kinetics. The concentration of EG was calculated using three kinetic parameters: a rate constant for the first-order formation of EG from serum ethanol, a transfer constant for an obstructed transfer of EG from the formation site (FS) into the central compartment (CC) and an exponential elimination constant. The program was applied to the data collected from 21 drinking experiments. The fitting algorithm optimized the three kinetic parameters, until the sum of concentration error squares of the data points was minimized. The means±standard deviation of the rate constant for the first-order formation of EG from serum ethanol was 0.0011±0.0006 h −1, the transfer constant for an obstructed transfer of EG from the FS into the CC was 0.43±0.1996 h −1 and the exponential elimination constant was 3.0±1.45 h −1. Using the range of these parameters, it is now possible to calculate minimum and maximum serum concentrations of EG based on ethanol doses and drinking times. The comparison of calculated and measured concentrations can prove the plausibility of an alleged ethanol consumption. This can be crucial when the serum ethanol concentration (SEC) itself is not meaningful.

Effects of Food and Body Composition on Blood Alcohol Curves

This chapter discusses the effects of food and body composition on the levels of blood alcohol. Sex and age differences in the pharmacokinetics of ethanol are largely explained by differences in body composition, and corresponding differences in volume of distribution of ethanol. When dosage is calculated on the basis of total body water, rather than on total body weight, the age and sexes differences virtually disappear. The suggestion that gastric first-pass metabolism of ethanol is a major source of sex difference in alcohol bioavailability— is not supported by the bulk of evidence of all kinds. First-pass metabolism, whether gastric or hepatic, plays a minimal role in determining the blood alcohol concentration achieved by ingestion of a given dose of ethanol. A controversy surrounding this topic is attributed to the use of ‘area under the curve’ measurements to estimate oral bioavailability, under conditions in which this method is not applicable. The relationship between blood alcohol levels and alcohol-related pathology is complex. Some types of pathology are related to the pathways of ethanol metabolism, and hence to the total amount of ethanol consumed within a day, a month, or some other given period of time.

Ethanol metabolism in the brain.

Acetaldehyde is suspected of being involved in the central mechanism of central nervous system depression and addiction to ethanol, but in contrast to ethanol, it can not penetrate easily from blood into the brain because of metabolic barriers. Therefore, the possibility of ethanol metabolism and acetaldehyde formation inside the brain has been one of the crucial questions in biomedical research of alcoholism. This article reviews the recent progress in this area and summarizes the evidence on the first stage of ethanol oxidation in the brain and the specific enzyme systems involved. The brain alcohol dehydrogenase and microsomal ethanol oxidizing systems, including cytochrome P450 II E1 and catalase are considered. Their physicochemical properties, the isoform composition, substrate specificity, the regional and subcellular distribution in CNS structures, their contribution to brain ethanol metabolism, induction under ethanol administration and the role in the neurochemical mechanisms of psychopharmacological and neurotoxic effects of ethanol are discussed. In addition, the nonoxidative pathway of ethanol metabolism with the formation of fatty acid ethyl esters and phosphatidylethanol in the brain is described.

Peroxisome proliferators increase ethanol catabolism through utilization of the catalase pathway

We investigated the effects of ciprofibrate, a potent peroxisome proliferator, on ethanol metabolism in mice. The blood alcohol levels of mice fed a liquid diet containing both ciprofibrate and ethanol were markedly depressed compared with mice fed the ethanol-containing diet alone. Ciprofibrate markedly induced enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, hydrogen peroxide, and to a lesser extent catalase in both control and ethanol-diet fed mice. Northern blot analysis indicated no significant upregulation of cytochrome P450IIE1 mRNA by ciprofibrate. Our study suggests that peroxisome proliferators increase ethanol catabolism through hydrogen peroxide production, thus allowing utilization of the catalase pathway. These findings indicate that catalase has the potential to provide a significant pathway for ethanol metabolism under conditions of peroxisome proliferation.

Induction of Cytochrome P‐4502E1 by Ethanol in Rat Kupffer Cells

Ethanol has been shown to affect several Kupffer cell functions, but the mechanisms underlying these changes are unknown. One possible mediator is cytochrome P-4502E1 (CYP2E1), an ethanol-inducible enzyme that has been associated with toxic effects in the liver, as well as in many extrahepatic organs. To assess whether CYP2E1 can be induced by ethanol in Kupffer cells, male rats pair-fed ethanol-containing or control Lieber-DeCarli diets for 3 weeks were studied. Immunoblotting experiments showed that ethanol-treatment caused a 7-fold increase in CYP2E1 content both in Kupffer cells and hepatocytes. When expressed per milligram of S9 protein, the content of CYP2E1 in Kupffer cells was, however, 10 times lower than in hepatocytes. Immunohistochemical studies revealed that CYP2E1 is located in the endoplasmic reticulum of Kupffer cells in vivo and that it is also present in isolated Kupffer cells. In both Kupffer cells and hepatocytes, ethanol feeding increased the hydroxylation of p-nitrophenol, a relatively specific substrate for CYP2E1, demonstrating that the induced CYP2E1 was catalytically active. This reaction was significantly inhibited by anti-CYP2E1 IgG in both types of cells. Although CYP2E1 may not be the predominant pathway for ethanol metabolism in hepatocytes, it is possibly the major one in Kupffer cells. Thus, the induction of CYP2E1 by ethanol in these cells could cause significant changes in intracellular acetaldehyde concentrations which, together with increased lipid peroxidation, may contribute to the development of alcoholic liver injury.

Metabolic interactions of 4-hydroxynonenal, acetaldehyde and glutathione in isolated liver mitochondria.

It is well documented that the metabolism of ethanol occurs through a series of pyridine nucleotide-linked enzymatic reactions resulting in the production of acetaldehyde and acetate. The factors regulating hepatic acetaldehyde oxidation are of critical importance, since ethanol-derived acetaldehyde has been implicated in hepatic lipid peroxidation. Isolated hepatocytes incubated in high concentrations of acetaldehyde exhibit significant increases in lipid peroxidation as measured by malondialdehyde formation (Stege, 1982); and the infusion of acetaldehyde to perfused rat liver also stimulates lipid peroxidation as measured by an increased formation of ethane (Muller and Sies, 1983). Recently an alternative pathway of ethanol metabolism has been identified which may also contribute to initiation of hepatic lipid peroxidation (Reinke, et al., 1991; and Knecht et al. 1990). Occurring independent of the pyridine nucleotide-linked dehydrogenase enzymes, this enzymatic pathway involves a P-450 mediated, one electron oxidation of ethanol resulting in the production of an ethanol-derived free radical which could serve as an initiator of lipid peroxidation.

Nonoxidative ethanol metabolism: Expression of fatty acid ethyl ester synthase-III in cultured neural cells

Alcohol metabolism in the human brain has been characterized as essentially nonoxidative in nature, with the esterification of ethanol with fatty acids via fatty acid ethyl ester synthase. This pathway of ethanol metabolism is related to end organ damage in the brain but the neural cell type expressing FAEES has not been identified. In this study human and rodent neuroblastoma and glioma cell lines are assayed for fatty acid ethyl ester synthase activity. Cells with neuronal properties demonstrated higher activity than glioma cell lines. We confirmed the presence of the mRNA for one type of synthase, fatty acid ethyl ester synthase-III in three neuronal cell lines - N1E115 cells, PC12 cells, and SK-N-MC cells. These results support the hypothesis that FAEES activity is expressed chiefly in cells with neuronal properties and suggest that non-oxidative ethanol metabolism is potentially related to the toxic effect of ethanol on the human brain.

Ethanol-induced fatty acid ethyl ester formation in vivo and in vitro in rat lung

Fatty acid ethyl esters (FAEE) are the end products of a non-oxidative pathway for ethanol metabolism in a variety of human, rabbit, rat and murine tissues. Our objective was to determine the significance of this pathway in the metabolism of ethanol by the rat lung. In vitro, 14C-labeled ethyl oleate formation was assayed in the lung and compared with the pancreas, liver, heart and brain. Lipids were extracted with acetone, and 14C-labeled ethyl oleate was isolated and quantified by thin layer chromatography (TLC) and scintillation spectrometry. FAEE synthetic activity in the lungs (in vitro) was found to be intermediate among the organs examined. In vivo, male rats received 10% ethanol in their drinking water with or without daily i.p. injections of 4-methylpyrazole (1 mmol/kg body wt) for 15 days. Another group of male rats received 4 g/kg body wt ethanol as a 50% (v/v) solution by gavage every 12 h for 2 days. FAEE from the three organs with the highest in vitro activity for FAEE synthesis (pancreas, liver and lung) were extracted with acetone, isolated from normal lipids by TLC and separated by gas chromatography. The lung had lower FAEE-forming activity than the pancreas or the liver in the 15-day studies. However, in the 2-day study, the lung had higher activity than the liver but lower activity than the pancreas. Ethyl oleate, ethyl stearate and ethyl palmitate were the predominant FAEE formed in the intact organism. Ethanol-induced FAEE may play a role in the development of alcohol-related injuries to the lung.

Synthesis and degradation of fatty acid ethyl esters by cultured hepatoma cells exposed to ethanol.

Fatty acid ethyl esters are a family of neutral lipids that are the products of esterification of fatty acids with ethanol. Unlike other pathways of ethanol metabolism, ethyl esters are present in numerous human organs which are the targets of ethanol-induced damage. In the present study, we have shown that fatty acid ethyl esters are synthesized by a hepatoma cell line in tissue culture when exposed to ethanol concentrations easily attained by man during social drinking. Unlike alcohol dehydrogenase, the enzyme(s) responsible for synthesis of ethyl esters are membrane-bound and concentrated in the microsomal fraction of rat hepatocytes. In addition, fatty acid ethyl esters are hydrolyzed to free fatty acids and ethanol by membrane-bound enzyme(s) that are enriched in the microsomal and mitochondrial-lysosomal fractions. Intracellular hydrolysis of fatty acid ethyl esters release free fatty acids which are preferentially incorporated into cellular cholesterol esters. Thus, we have shown that a hepatocellular line exposed to concentrations of ethanol easily achieved in man by social drinking utilize endogenous fatty acids to form long-lived ethanol metabolites, fatty acid ethyl esters. Importantly, this family of neutral lipids may act as biochemical mediators of ethanol-induced cell damage, including the changes in cholesterol metabolism noted in chronic alcoholics.

INTERACTION OF ETHANOL WITH DRUGS, HEPATOTOXIC AGENTS, CARCINOGENS AND VITAMINS

Ethanol has been shown to have a multitude of acute and chronic interactions with xenobiotic agents, many of which can now be explained on the basis of the existence of a newly recognized microsomal ethanol oxidizing system (MEOS) involving a specific cytochrome P-450 (P450IIE1). Although such a system was proposed already two decades ago, its role was viewed with skepticism: until recently, it was commonly believed that the primary pathway for hepatic ethanol metabolism is due almost exclusively to the activity of cytosolic alcohol dehydrogenase, with a minor contribution from peroxisomal catalase. It is now recognized, however, that liver microsomes (through MEOS) participate in ethanol metabolism. The existence of this system and its inducibility contribute to the metabolic tolerance to ethanol in the alcoholic. Cross induction of other microsomal enzymes also explains the tolerance to many commonly used drugs. Most importantly, the alcohol-inducible form (P450IIE1) has a unique capacity to activate xenobiotic agents to toxic metabolites, thereby explaining the unusual susceptibility of the alcoholic to the adverse effects of other drugs, hepatotoxic agents, carcinogens and even vitamins.