First-pass Metabolism Of Ethanol Research Articles

Intestine-Liver Axis On-Chip Reveals the Intestinal Protective Role on Hepatic Damage by Emulating Ethanol First-Pass Metabolism.

Intestine-Liver-on-chip systems can be useful to predict oral drug administration and first-pass metabolism in vitro in order to partly replace the animal model. While organ-on-chip technology can count on sophisticated micro-physiological devices, the engineered organs still remain artificial surrogates of the native counterparts. Here, we used a bottom-up tissue engineering strategy to build-up physiologically functional 3D Human Intestine Model (3D-HIM) as well as 3D Liver-microtissues (HepG2-μTPs) in vitro and designed a microfluidic Intestine-Liver-On-Chip (InLiver-OC) to emulate first-pass mechanism occurring in vivo. Our results highlight the ethanol-induced 3D-HIM hyper-permeability and stromal injury, the intestinal prevention on the liver injury, as well as the synergic contribution of the two 3D tissue models on the release of metabolic enzymes after high amount of ethanol administration.

Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration.

Acetaldehyde (ACH) associated with alcoholic beverages is Group 1 carcinogen to humans (IARC/WHO). Aldehyde dehydrogenase (ALDH2), a major ACH eliminating enzyme, is genetically deficient in 30–50% of Eastern Asians. In alcohol drinkers, ALDH2-deficiency is a well-known risk factor for upper aerodigestive tract cancers, i.e., head and neck cancer and esophageal cancer. However, there is only a limited evidence for stomach cancer. In this study we demonstrated for the first time that ALDH2 deficiency results in markedly increased exposure of the gastric mucosa to acetaldehyde after intragastric administration of alcohol. Our finding provides concrete evidence for a causal relationship between acetaldehyde and gastric carcinogenesis. A plausible explanation is the gastric first pass metabolism of ethanol. The gastric mucosa expresses alcohol dehydrogenase (ADH) enzymes catalyzing the oxidation of ethanol to acetaldehyde, especially at the high ethanol concentrations prevailing in the stomach after the consumption of alcoholic beverages. The gastric mucosa also possesses the acetaldehyde-eliminating ALDH2 enzyme. Due to decreased mucosal ALDH2 activity, the elimination of ethanol-derived acetaldehyde is decreased, which results in its accumulation in the gastric juice. We also demonstrate that ALDH2 deficiency, proton pump inhibitor (PPI) treatment, and L-cysteine cause independent changes in gastric juice and salivary acetaldehyde levels, indicating that intragastric acetaldehyde is locally regulated by gastric mucosal ADH and ALDH2 enzymes, and by oral microbes colonizing an achlorhydric stomach. Markedly elevated acetaldehyde levels were also found at low intragastric ethanol concentrations corresponding to the ethanol levels of many foodstuffs, beverages, and dairy products produced by fermentation. A capsule that slowly releases L-cysteine effectively eliminated acetaldehyde from the gastric juice of PPI-treated ALDH2-active and ALDH2-deficient subjects. These results provide entirely novel perspectives for the prevention of gastric cancer, especially in established risk groups.

Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: Assessment of the effects on first-pass metabolism of ethanol

Previous studies have reported that aspirin significantly reduced the first-pass metabolism (FPM) of ethanol in humans thereby increasing adverse effects of alcohol. The underlying causes, however, remain poorly understood. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions. We investigated the inhibition profiles by aspirin and its major metabolite salicylate of ethanol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and acetaldehyde oxidation by ALDH1A1 and ALDH2, at pH 7.5 and 0.5mM NAD+. Competitive inhibition pattern was found to be a predominant type among the ADHs and ALDHs studied, although noncompetitive and uncompetitive inhibitions were also detected in a few cases. The inhibition constants of salicylate for the ADHs and ALDHs were considerably lower than that of aspirin with the exception of ADH1A that can be ascribed to a substitution of Ala-93 at the bottom of substrate pocket as revealed by molecular docking experiments. Kinetic inhibition equation-based simulations show at higher therapeutic levels of blood plasma salicylate (1.5mM) that the decrease of activities at 2–10mM ethanol for ADH1A/ADH2 and ADH1B2/ADH1B3 are predicted to be 75–86% and 31–52%, respectively, and that the activity decline for ALDH1A1 and ALDH2 at 10–50μM acetaldehyde to be 62–73%. Our findings suggest that salicylate may substantially inhibit hepatic FPM of alcohol at both the ADH and ALDH steps when concurrent intaking aspirin.

Sa1863 L-Cysteine Slow-Release Capsule Formulation in Prevention of Gastric Carcinogenesis Associated With Atrophic Gastritis

INTRODUCTION: Atrophic gastritis (AG) with concomitant acid-free or hypochlorhydric stomach and Helicobacter pylori infection are the two most important risk factors for gastric cancer. Gastric mucosa, many microbes colonizing acid-free stomach and H. pylori strains possess alcohol dehydrogenase activity capable of locally producing acetaldehyde (ACH) from ethanol. ACH produced from ethanol in oral cavity contributes to gastric ACH exposure via saliva. Limited capacity of mucosal cells and microbes to eliminate ACH, results in enhanced exposure of gastric mucosa to the carcinogenic actions of ACH. ACH associated with alcoholic beverages has been classified as carcinogenic (Group 1) to humans by IARC/ WHO. Capsule that slowly releases L-cysteine in the stomach converting ACH to inactive 4-methyltiazolidine-2-carboxylic acid (MTCA) has been recently implicated in prevention of gastric carcinogenesis among patients with AG. AIMS: To assess the production of ACH and MTCA in the stomach of AG patients following an exposure to 15% ethanol, with or without administration of L-cysteine. METHODS: Seven H.pylori positive patients, selected among 42 subjects with biopsy-confirmed AG, and fasting serum levels of pepsinogen (PG) I 10 pmol/L participated in the study. In a single-blinded fashion and on two separate days, patients were intubated with a nasogastric tube and exposed to15 % ethanol (0.3g/kg) and randomly 200 mg of L-cysteine or placebo. Gastric juice samples (5mL) were drawn every 20 min over a period of 4 hours and analyzed for pH and ACH-, ethanol-, L-cysteineand MTCA-concentrations. ACH and ethanol were analyzed by headspace gas chromatography and L-cysteineand MTCA-levels by liquid chromatography coupled to a triple-quadropole mass spectrometer. RESULTS: After intake of L-cysteine, free ACH levels in gastric juice decreased by a mean of 76% for 20 to 100min (p=0.0023, <0.0001, 0.0086, 0.0102 at 20-, 40-, 60and 100min, respectively). After placebo, peak ACH levels ranged from 11.5 to 52.7μM as compared to 1.5 to 20.2μM following L-cysteine. In gastric juice, the mean peak L-cysteine level was 11928μM at 40min and mean peak MTCA level 1824μM at 80min. At 80min after intake of L-cysteine MTCA level was 654-fold as compared with free ACH level in gastric juice. CONCLUSIONS: The first-pass metabolism of ethanol mediated by gastric mucosal cells and/or microbes results in a marked exposure of gastric mucosa to ACH. Without L-cysteine, ACH is distributed to local water phase and metabolized further to acetate by gastric mucosal low Km ALDH enzymes. As shown by high MTCA levels in gastric juice after ethanol and slow releasing L-cysteine, it can be calculated that up to 90 % of locally formed ACH is inactivated by Lcysteine, thus significantly reducing the exposure to carcinogenic acetaldehyde.

Sa1866 Timing of Antibiotics to Prevent Gastric Cancer in a Mouse Model of H. pylori Infection

INTRODUCTION: Atrophic gastritis (AG) with concomitant acid-free or hypochlorhydric stomach and Helicobacter pylori infection are the two most important risk factors for gastric cancer. Gastric mucosa, many microbes colonizing acid-free stomach and H. pylori strains possess alcohol dehydrogenase activity capable of locally producing acetaldehyde (ACH) from ethanol. ACH produced from ethanol in oral cavity contributes to gastric ACH exposure via saliva. Limited capacity of mucosal cells and microbes to eliminate ACH, results in enhanced exposure of gastric mucosa to the carcinogenic actions of ACH. ACH associated with alcoholic beverages has been classified as carcinogenic (Group 1) to humans by IARC/ WHO. Capsule that slowly releases L-cysteine in the stomach converting ACH to inactive 4-methyltiazolidine-2-carboxylic acid (MTCA) has been recently implicated in prevention of gastric carcinogenesis among patients with AG. AIMS: To assess the production of ACH and MTCA in the stomach of AG patients following an exposure to 15% ethanol, with or without administration of L-cysteine. METHODS: Seven H.pylori positive patients, selected among 42 subjects with biopsy-confirmed AG, and fasting serum levels of pepsinogen (PG) I 10 pmol/L participated in the study. In a single-blinded fashion and on two separate days, patients were intubated with a nasogastric tube and exposed to15 % ethanol (0.3g/kg) and randomly 200 mg of L-cysteine or placebo. Gastric juice samples (5mL) were drawn every 20 min over a period of 4 hours and analyzed for pH and ACH-, ethanol-, L-cysteineand MTCA-concentrations. ACH and ethanol were analyzed by headspace gas chromatography and L-cysteineand MTCA-levels by liquid chromatography coupled to a triple-quadropole mass spectrometer. RESULTS: After intake of L-cysteine, free ACH levels in gastric juice decreased by a mean of 76% for 20 to 100min (p=0.0023, <0.0001, 0.0086, 0.0102 at 20-, 40-, 60and 100min, respectively). After placebo, peak ACH levels ranged from 11.5 to 52.7μM as compared to 1.5 to 20.2μM following L-cysteine. In gastric juice, the mean peak L-cysteine level was 11928μM at 40min and mean peak MTCA level 1824μM at 80min. At 80min after intake of L-cysteine MTCA level was 654-fold as compared with free ACH level in gastric juice. CONCLUSIONS: The first-pass metabolism of ethanol mediated by gastric mucosal cells and/or microbes results in a marked exposure of gastric mucosa to ACH. Without L-cysteine, ACH is distributed to local water phase and metabolized further to acetate by gastric mucosal low Km ALDH enzymes. As shown by high MTCA levels in gastric juice after ethanol and slow releasing L-cysteine, it can be calculated that up to 90 % of locally formed ACH is inactivated by Lcysteine, thus significantly reducing the exposure to carcinogenic acetaldehyde.

Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol

Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mm NAD+. Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (Kis) ranging from 0.90 mm (ADH2) to 20 mm (ADH1A), and the intercept inhibition constants (Kii) ranging from 1.4 mm (ADH1C allozymes) to 19 mm (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (Kis = 3.0 mm and Kii = 2.2 mm), but competitive inhibition for ALDH1A1 (Kis = 0.96 mm). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2–0.5 mm) and physiologically relevant concentrations of ethanol (10 mm) and acetaldehyde (10 μm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12–26%) and ADH2 (14–28%) in the liver and small intestine, ADH4 (15–31%) in the stomach, and ALDH1A1 (16–33%) and ALDH2 (8.3–19%) in all 3 tissues. The results suggest that inhibition by acetaminophen of hepatic and gastrointestinal FPM of ethanol through ADH and ALDH pathways might become significant at higher, subtoxic levels of acetaminophen.

Individual Differences in Blood Alcohol Concentrations after Moderate Drinking Are Mainly Regulated by Gastric Emptying Rate Together with Ethanol Distribution Volume

Blood alcohol concentration (BAC) differs greatly among individuals, even when people of the same sex and age drink alcohol under the same drinking conditions. In this study, we investigated the main factors involved in the internal reg-ulation of individual differences in BAC, focusing on the alcohol dehydrogenase 1B (ADH1B) genotype, blood acetal-dehyde concentration (BAcH), amount of habitual alcohol consumption, pharmacokinetic parameters of BAC, distribution volume of ethanol (Vd), and gastric emptying rate (GER) under the same drinking conditions. Twenty healthy Japanese males aged between 40 and 59 years old and having the aldehyde dehydrogenase 2 (ALDH2) genotype of ALDH 2*1/*2 were recruited for this study. The subjects were given 0.32 g ethanol/kg body weight in the form of commercially available beer (5%, v/v). The results showed that BAC-max differed greatly among individuals with a more than two-fold variation. When the BAC-time curve was compared among ADH1B genotypes (ADH1B*1/*1, *1/*2, and *2/*2), there were no differences in BAC among the genotypes. Although BAcH, monthly alcohol consumption, elimination rate of blood ethanol (β value) and ethanol disappearance rate from the body (EDR) can affect BAC, all of them had no correlations with BAC-max. However, Vd (liter/kg), ΔPlasma glucose concentration (ΔPGC = PGC30 min ? PGC0 min) and the serum concentration of gastric inhibitory polypeptide (GIP) did correlate with BAC-max. Model 2 in multiple linear regression analysis showed the optimal model for Vd and GIP with positive correlations with BAC-max. As GIP and ΔPGC are both reflected by gastric emptying rate (GER), we concluded that the individual differences in BAC after moderate drinking are mainly regulated by GER together with Vd. These findings demonstrate that together with body water content, the gastrointestinal tract plays an important role in the regulation of individual differences in BAC, involving first pass metabolism of ethanol.

Tissue-distribution of aldehyde dehydrogenase 2 and effects of the Aldh2 gene-disruption on the expression of enzymes involved in alcohol metabolism

In alcohol metabolism, acetaldehyde, a highly reactive intermediate that may cause cellular and DNA damages, is converted to acetate by mitochondrial aldehyde dehydrogenase ALDH2. Although the majority of ingested alcohol is eliminated in the liver, the first-pass metabolism of ethanol in the upper digestive tract is also important for prevention and management of ethanol-related gastrointestinal diseases. However, the tissue-distribution of Aldh2 in mice has been poorly investigated. In this study, therefore, we investigated the tissue-distribution of Aldh2 as well as Aldh1, Cyp1a1, Cyp2e1, and Cyp4b1 in wild type and Aldh2-null mice by immuno-histochemical analysis. The human liver and esophageal tissues were also examined. In mice, the Aldh2 protein was detected in the liver, lung, heart, kidney, testis, esophagus, stomach, colon, and pancreas, suggesting that the tissue-distribution of Aldh2 in mice is similar to that in humans. Therefore, Aldh2-null mice may be useful model animals for the investigation of alcohol metabolism and related diseases. Compared with the wild type, the expression level of Cyp2e1 was increased in the liver from Aldh2-null mice based on Western blot analysis, whereas the levels of Aldh1, Cyp1a1, and Cyp4b1 were indistinguishable. This observation suggests that a metabolite(s) of Aldh2 might down-regulate the expression of Cyp2e1 gene.

Alcohol metabolism: role in toxicity and carcinogenesis.

This article contains the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, organized and co-chaired by Thomas M. Badger, Paul Shih-Jiun Yin, and Helmut Seitz. The presentations were (1) First-pass metabolism of ethanol: Basic and clinical aspects, by Charles Lieber; (2) Intracellular CYP2E1 transport, oxidative stress, cytokine release, and ALD, by Magnus Ingelman-Sundberg; (3) Pulsatile ethanol metabolism in intragastric infusion models: Potential role in toxic outcomes, by Thomas M. Badger and Martin J.J. Ronis; (4) Free radicals, adducts, and autoantibodies resulting from ethanol metabolism: Role in ethanol-associated toxicity, by Emanuele Albano; and (5) Gastrointestinal metabolism of ethanol and its possible role in carcinogenesis, by Helmut Seitz.

Mammalian alcohol dehydrogenase - functional and structural implications.

Mammalian alcohol dehydrogenase (ADH) constitutes a complex system with different forms and extensive multiplicity (ADH1-ADH6) that catalyze the oxidation and reduction of a wide variety of alcohols and aldehydes. The ADH1 enzymes, the classical liver forms, are involved in several metabolic pathways beside the oxidation of ethanol, e.g. norepinephrine, dopamine, serotonin and bile acid metabolism. This class is also able to further oxidize aldehydes into the corresponding carboxylic acids, i.e. dismutation. ADH2, can be divided into two subgroups, one group consisting of the human enzyme together with a rabbit form and another consisting of the rodent forms. The rodent enzymes almost lack ethanol-oxidizing capacity in contrast to the human form, indicating that rodents are poor model systems for human ethanol metabolism. ADH3 (identical to glutathione-dependent formaldehyde dehydrogenase) is clearly the ancestral ADH form and S-hydroxymethylglutathione is the main physiological substrate, but the enzyme can still oxidize ethanol at high concentrations. ADH4 is solely extrahepatically expressed and is probably involved in first pass metabolism of ethanol beside its role in retinol metabolism. The higher classes, ADH5 and ADH6, have been poorly investigated and their substrate repertoire is unknown. The entire ADH system can be seen as a general detoxifying system for alcohols and aldehydes without generating toxic radicals in contrast to the cytochrome P450 system.

Contribution of Gastric Oxidation to Ethanol First-Pass Metabolism in Baboons

Contribution of Gastric Oxidation to Ethanol First-Pass Metabolism in Baboons

Alcohol and drug interactions

Alcohol metabolism occurs mainly in the liver, where in abstainers the alcoholdehydrogenase (ADH) pathway plays the major role. After chronic alcohol consumption, the microsomal ethanol-oxidizing system (MEOS), involving the ethanol-inducible cytochrome P450 2E1, increases in importance with a four- to ten-fold increase in the contribution to alcohol metabolism. Because of the fact that this enzyme system catalyses not only the metabolism of ethanol but also activates a great number of drugs, it is a very common site of alcohol-drug interactions. Clinically relevant interactions will be discussed. Only a small amount of alcohol is metabolized outside the liver, mainly in the stomach by gastric ADH, which leads to the so-called first-pass metabolism of ethanol. Its significance in alcohol metabolism is reviewed. The only way to prevent severe alcohol-drug interactions is to make medical doctors as well as their patients more aware of these possible secondary effects.

Alcohol levels are increased in social drinkers receiving ranitidine.

Ranitidine increases blood alcohol concentrations by decreasing the first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has been found to be variable when using large doses of alcohol or conditions in which its first pass metabolism is known to be minimal. Despite a consensus that the drug increases alcohol levels after small doses of ethanol, this effect has been considered inconsequential, because of the low alcohol levels. However, social drinking comprises repetitive consumption of small doses of alcohol and the ranitidine effect could thereby be potentiated. To study this factor, alcohol levels were determined by breath analysis in nine men (social drinkers), after four drinks of 0.15 g/kg ethanol given postprandially every 45 min, before and after ranitidine (150 mg b.i.d. for 7 days). Their blood alcohol increased with repeated doses, reaching peak values of 24+/-3 mg/dl before ranitidine and 33+/-2 after ranitidine (p = 0.04). In seven of the nine subjects blood alcohol exceeded 25 mg/dl, a level at which impairment of judgment and of finely tuned skills occurs and which exceeds legal limits of driving in some European countries. Moreover, the high levels persisted for a longer time with than without the drug. These effects were associated with a 62% decrease in first pass metabolism. Under conditions mimicking social drinking, ranitidine increases blood alcohol to levels known to impair psychomotor skills needed for driving.

Alcohol levels are increased in social drinkers receiving ranitidine

OBJECTIVE: Ranitidine increases blood alcohol concentrations by decreasing the first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has been found to be variable when using large doses of alcohol or conditions in which its first pass metabolism is known to be minimal. Despite a consensus that the drug increases alcohol levels after small doses of ethanol, this effect has been considered inconsequential, because of the low alcohol levels. However, social drinking comprises repetitive consumption of small doses of alcohol and the ranitidine effect could thereby be potentiated. METHODS: To study this factor, alcohol levels were determined by breath analysis in nine men (social drinkers), after four drinks of 0.15 g/kg ethanol given postprandially every 45 min, before and after ranitidine (150 mg b.i.d. for 7 days). RESULTS: Their blood alcohol increased with repeated doses, reaching peak values of 24 ± 3 mg/dl before ranitidine and 33 ± 2 after ranitidine ( p = 0.04). In seven of the nine subjects blood alcohol exceeded 25 mg/dl, a level at which impairment of judgment and of finely tuned skills occurs and which exceeds legal limits of driving in some European countries. Moreover, the high levels persisted for a longer time with than without the drug. These effects were associated with a 62% decrease in first pass metabolism. CONCLUSION: Under conditions mimicking social drinking, ranitidine increases blood alcohol to levels known to impair psychomotor skills needed for driving.

Nitric oxide-mediated regulation of gastric H+, K+ -ATPase and alcohol dehydrogenase following ethanol-induced injury in rats.

The mucosal protective effect of nitric oxide (NO) was examined by using N(G)-nitro-L-arginine methyl ester (L-NAME) as nitric oxide synthase (NOS) inhibitor and nitroprusside (NP) as NO donating agent, in ethanol-induced rat gastric lesion model. The results are summarized as follows: (1) As gastric tissue samples were examined by light microscopy, intragastric exposure of ethanol was demonstrated to induce gastric injury, which was more prominent in female rats. The depletion of NO by L-NAME treatment exacerbated the ethanol-induced gastric lesion but NP together with ethanol promoted repair of the mucosal injury, especially in female rats. (2) Gastric H+, K+ -ATPase enzyme activity, which was responsible for acid secretion, seemed not to be effected by ethanol treatment. Together with ethanol, L-NAME treatment activated, whereas NP treatment inhibited, the enzyme activity in female rats. (3) Ethanol treatment inhibited gastric alcohol dehydrogenase (ADH) activity, which was responsible for the first-pass metabolism of ethanol. Together with ethanol, L-NAME did not effect the enzyme activity whereas NP treatment disappeared the inhibitory effect of ethanol in both gender. Hydroxyl radical (OH*) scavenger activity was found to increase in ethanol and ethanol + NP groups in both sexes, but superoxide radical (O2-*) scavenger activity did not change. The results indicate that NO may ameliorate the damaging effect of ethanol possibly by regulating acid secretion, ethanol metabolism, and antioxidant content in rat gastric mucosa.

Helicobacter pylori Infection Decreases Gastric Alcohol Dehydrogenase Activity and First-Pass Metabolism of Ethanol in Man

Background/Aims: Ethanol is metabolized by alcohol dehydrogenase in the human stomach. This metabolism contributes to the so-called first-pass metabolism of ethanol which is affected by gender, medication, and morphological alterations of the gastric mucosa. Recently, it has been shown that Helicobacter pylori is capable to oxidize ethanol to acetaldehyde in vitro. Since H. pylori also injures gastric mucosa, the present study examines the effect of this bacterium on gastric alcohol dehydrogenase activity and systemic availability of ethanol in vivo. Methods: Thirteen volunteers (7 men and 6 women, aged 18–52 years) with gastric H. pylori infection diagnosed by a positive CLO test and positive gastric histology received ethanol (0.225 g/kg) either orally or intravenously before and after H. pylori elimination to determine systemic availability of ethanol. In addition, gastric biopsy specimens were taken from all subjects before and after H. pylori elimination for histological assessment of mucosal alterations and determinations of gastric alcohol dehydrogenase activity and phenotype of the enzyme. Results: In the presence of H. pylori the first-pass metabolism of ethanol was found to be significantly reduced (625 ± 234 vs. 1,155 ± 114 mg/dl/min, p = 0.046). This reduction of first-pass metabolism of ethanol was associated with a significant decrease in alcohol dehydrogenase activity (4.8 ± 1.5 vs. 12.1 ± 2.3 nmol/mg protein × min, p < 0.05) and an increase in the severity of mucosal damage as determined by a histological score (p < 0.05). Conclusions: H. pylori infection leads to gastric mucosal injury which is associated with a decrease in gastric alcohol dehydrogenase activity and first-pass metabolism of ethanol. Ethanol metabolism by H. pylori does not play an important role in vivo. However, gastric morphology is one important factor determining systemic availability of ethanol in man.

Omeprazole, ranitidine, and cimetidine have no effect on peak blood ethanol concentrations, first pass metabolism or area under the time-ethanol curve under 'real-life' drinking conditions.

Considerable controversy persists over the influence of H2-receptor antagonists on the first pass clearance of ethanol. The majority of previously published studies have studied the effects of the drugs on low-dose ethanol in the fasting state. We elected to study the possible interaction under simulated real-life conditions. Twenty-three volunteers were given 0.6 g/kg body weight ethanol in the form of 4.8% beer following a standardized meal. Blood ethanol levels were measured over the next 3 h. Studies were repeated using ethanol administered as an intravenous infusion while subjects consumed the same volume of de-alcoholized beer. The effects of a minimum of 2 weeks of dosing with cimetidine, ranitidine and omeprazole were examined. Following food, and with ethanol taken in the form of beer, mean first pass metabolism of ethanol was 58% (range 34-78%). No statistically significant difference was found following drug treatment in either percentage first pass metabolism, peak blood ethanol concentration or area under the time-blood ethanol curve. Under these 'real-life' conditions, the concomitant administration of cimetidine, ranitidine or omeprazole is unlikely to have significant physical, social or forensic implications, since they do not significantly change ethanol elimination.

Zinc Administration Improves Gastric Alcohol Dehydrogenase Activity and First-Pass Metabolism of Ethanol in Alcohol-Fed Rats

Zinc Administration Improves Gastric Alcohol Dehydrogenase Activity and First-Pass Metabolism of Ethanol in Alcohol-Fed Rats

The role of gastrointestinal factors in alcohol metabolism.

Although the liver is the major organ responsible for ethanol metabolism, such metabolism also occurs in the gastrointestinal (GI) tract. However, compared to the liver, GI metabolism of ethanol is quantitatively much lower. Various enzyme systems have been characterized in GI mucosal cells including various isozymes of alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP 2E1) and catalase. Gastric ADH activity is one factor by which first pass metabolism (FPM) is influenced and its activity is modulated by genetics, gender, age, drugs and gastric morphology. Another important factor in FPM of ethanol is the speed of gastric emptying. In addition to mucosal ethanol metabolism, ethanol can also be oxidized by many bacterial species in the upper GI tract including oropharynx and stomach as well as in the large intestine. GI metabolism of ethanol may influence systemic bioavailability of ethanol and may lead to local toxicity most likely mediated by acetaldehyde. Such toxicity could be of importance in ethanol-associated carcinogenesis.

First pass metabolism of ethanol: gastric or hepatic, mountain or molehill?

HepatologyVolume 25, Issue 5 p. 1292-1294 Hepatology ElsewhereFree Access First pass metabolism of ethanol: Gastric or hepatic, mountain or molehill? D W Crabb, D W CrabbSearch for more papers by this author D W Crabb, D W CrabbSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510250543Citations: 16AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume25, Issue5May 1997Pages 1292-1294 ReferencesRelatedInformation