Gastric Alcohol Dehydrogenase Research Articles

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.

The alcohol dehydrogenase isoenzyme alcohol dehydrogenase IV as a candidate marker of Helicobacter pylori infection.

IntroductionHelicobacter pylori infection is associated with decreased alcohol dehydrogenase (ADH) activity in the gastric mucosa. The decrease in gastric ADH activity depends on the severity of inflammation and mucosal injury. This damage can be a reason of the release of enzyme from gastric mucosa and leads to the increase of the ADH activity in the sera of patients with H. pylori infection.Material and methodsSerum samples were taken from 140 patients with H. pylori infection. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline as a substrate and ALDH activity by the fluorometric method with 6-methoxy-2-naphtaldehyde. For the measurement of the activity of class I and II isoenzymes we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as a substrate.ResultsThe activity of ADH IV in the serum of patients with H. pylori infection increased about 42% (7.86 mU/l) in the comparison to the control level (4.52 mU/l). Total activity of ADH was 1105 mU/l in patients group and 682 mU/l in control. The diagnostic sensitivity for ADH IV was 88%, specificity 90%, positive and negative predictive values were 91% and 84% respectively. Area under ROC curve for ADH IV was 0.84.ConclusionsHelicobacter pylori infection of gastric mucosa is reflected in the serum by significant increase of class IV and total ADH activity. The results suggest a potential role for ADH IV as a marker of H. pylori infection.

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.

Retinaranitidine as an alcohol dehydrogenase inhibitor in acute methanol toxicity in rats

Methanol poisoning is a hazardous intoxication characterized by visual impairment and formic acidemia. The therapy for methanol poisoning is alcohol dehydrogenase (ADH) inhibitors to prevent formate accumulation. Ranitidine has been considered to be an inhibitor of both gastric alcohol and hepatic aldehyde dehydrogenase enzymes. This study aimed at testing ranitidine as an antidote for methanol acute toxicity and comparing it with ethanol and 4- methyl pyrazole (4-MP). This study was conducted on 48 Sprague -Dawley rats, divided into 6 groups, 8 rats in each group (one negative control group (C1), two positive control groups (C2, C3) and three test groups (1, 2 and 3). C2., C3 and all test groups were exposed to nitrous oxide by inhalation then, C3 group was given methanol (3 g/kg orally). The three test groups 1, 2 and 3 were given ethanol (0.5 g/kg orally), 4- MP (15 mg/kg intraperitoneally) and ranitidine (30 mg/kg intraperitoneally), respectively 4 h after giving methanol. Rats were sacrificed and heparinized, cardiac blood samples were collected for blood gases. Non-heparinized blood samples were collected for formate levels by high performance liquid chromatography. Eye balls were enucleated for histological examination of the retina. Ranitidine improved metabolic acidosis (p = 0.025), decreased formate levels (p = 0.014) and improved the histological findings in the retina induced by acute methanol toxicity. Key words: Ranitidine, methanol, poisoning, ethanol, rats.

Ranitidine as an alcohol dehydrogenase inhibitor in acute methanol toxicity in rats

Methanol poisoning is a hazardous intoxication characterized by visual impairment and formic acidemia. The therapy for methanol poisoning is alcohol dehydrogenase (ADH) inhibitors to prevent formate accumulation. Ranitidine has been considered to be an inhibitor of both gastric alcohol and hepatic aldehyde dehydrogenase enzymes. This study aimed at testing ranitidine as an antidote for methanol acute toxicity and comparing it with ethanol and 4-methyl pyrazole (4-MP). This study was conducted on 48 Sprague-Dawley rats, divided into 6 groups, with 8 rats in each group (one negative control group [C1], two positive control groups [C2, C3] and three test groups [1, 2 and 3]). C2, C3 and all test groups were exposed to nitrous oxide by inhalation, then, C3 group was given methanol (3 g/kg orally). The three test groups 1, 2 and 3 were given ethanol (0.5 g/kg orally), 4-MP (15 mg/kg intraperitoneally) and ranitidine (30 mg/kg intraperitoneally), respectively, 4 hours after giving methanol. Rats were sacrificed and heparinized, cardiac blood samples were collected for blood pH and bicarbonate. Non-heparinized blood samples were collected for formate levels by high performance liquid chromatography. Eye balls were enucleated for histological examination of the retina. Ranitidine corrected metabolic acidosis (p = .025), decreased formate levels (p = .014) and improved the histological findings in the retina induced by acute methanol toxicity.

Effects of a hexane extract from Laurus novocanariensis leaves on the ethanol metabolism of Wistar rats

A hexane extract from the leaves of Laurus novocanariensis was investigated for its activity on ethanol metabolism in Wistar rats. The extract could interfere with blood ethanol elevation, the induction of gastric alcohol dehydrogenase (ADH) and the reduction of erythrocyte catalase (CAT). The sesquiterpene lactones dehydrocostus lactone and costunolide were identified in the active extract, and might represent its active constituents. These results support the use of L. novocanariensis in the traditional Madeira Island medicine to protect against ethanol injury.

Key Role of Ethanol‐Derived Acetaldehyde in the Motivational Properties Induced by Intragastric Ethanol: A Conditioned Place Preference Study in the Rat

Acetaldehyde (ACD), the first metabolite of ethanol (EtOH), is produced peripherally by gastric and hepatic alcohol dehydrogenase (ADH) and centrally by brain catalase. In spite of the aversive properties classically ascribed to ACD, it has recently been suggested that ACD might mediate some of the motivational effects of EtOH. Accordingly, the relative role of ACD in the positive motivational properties of EtOH ingested is increasingly becoming the matter of debate. Thus, we studied the ability of intragastrically administered EtOH, ACD and EtOH-derived ACD to induce conditioned place preference (cpp) in rats. Wistar rats were pretreated intraperitoneally with saline, the peripheral competitive inhibitor of ADH, 4-methylpyrazole (4-MP, 22.5, 45 or 67.5 mg/kg) or with the selective ACD-sequestrating agent, d-penicillamine (DP, 25 or 50 mg/kg), before the intragastric administration of saline, EtOH (0.5, 1 or 2 g/kg) or ACD (10, 20, or 40 mg/kg). The specificity of 4-MP and DP effects was addressed using morphine-induced cpp (2.5 mg/kg). Both, EtOH and ACD dose-dependently induced cpp; further, while EtOH-induced cpp was prevented by the administration of 4-MP and by DP, ACD-induced cpp was unaltered by 4-MP administration and prevented by DP. Both pretreatments did not interfere with morphine-induced cpp indicating that 4-MP and DP specifically modulate the motivational properties of EtOH and ACD. The ability of 4-MP and DP to decrease EtOH-induced cpp suggests that a reduction of ACD levels is crucial in depriving EtOH from its motivational properties as indexed by the cpp procedure. In addition, this conclusion is supported by the inefficacy of 4-MP in preventing ACD-induced cpp, and by its blockade observed after administration of the selective ACD sequestrating agent DP. The present results underscore the role of EtOH-derived ACD in EtOH-induced motivational properties as well as its abuse liability.

Association of the gastric alcohol dehydrogenase gene ADH7 with variation in alcohol metabolism

Seven alcohol-metabolizing enzymes are encoded by the human alcohol dehydrogenase (ADH) gene cluster on chromosome 4q22-23. One of these genes, ADH7, is uniquely expressed in the stomach mucosa and can influence metabolism of alcohol before its absorption into the blood. However, the contribution of ADH7 to the overall genetic variation in alcohol oxidation in vivo is unknown. Data on in vivo alcohol metabolism were obtained for 206 Australian twin pairs of Caucasian ancestry, following ingestion of a standard dose (0.75 g kg(-1) body weight) of alcohol. Twenty-five single nucleotide polymorphisms that cover the ADH7 encoding region were genotyped. The patterns of linkage disequilibrium among these SNPs identified a recombinational hotspot within intron 7 of the ADH7 gene. A model for the absorption and elimination of alcohol from the body led to the identification of haplotypes associated with inter-individual variation in the early stages of alcohol metabolism. These are within a 35 kb DNA tract contained in the region 5' of intron 7 in the ADH7 gene. The region accounts for 18% of the linkage for alcohol concentration associated with the ADH region, or approximately 11% of the genetic variance.

Alcohol Dehydrogenase (ADH) Isoenzyme Activity in the Sera of Patients with Helicobacter pylori Infection

Human gastric mucosa contains three classes of alcohol dehydrogenase (ADH) isoenzymes: I, III, and IV. Various factors have been found to influence gastric ADH activity. One of them is Helicobacter pylori infection, which is associated with gastric mucosal injury and leads to a decrease in gastric ADH activity. The aim of the study was to assess the effect of H. pylori infection on the serum activity of ADH isoenzymes. Serum samples were taken from 35 patients with H. pylori infection and from 35 healthy subjects. For measurement of class I isoenzyme activity we employed the fluorometric method, with class-specific fluorogenic substrate (4-methoxy-1-naphthaldehyde). The activities of class III and IV ADH isoenzymes were measured by the photometric method with formaldehyde and with m-nitrobenzaldehyde as substrate, respectively. Total activity of ADH was measured by a photometric method with p-nitrosodimethylaniline. The total activities of ADH and class IV isoenzyme were significantly higher in sera of patients with H. pylori infection compared to healthy subjects. The serum activity of other tested isoenzymes of ADH did not differ significantly between infected and noninfected groups. We conclude that H. pylori infection of gastric mucosa is reflected in the serum by a significant increase in class IV and total ADH activity.

Nicotine Decreases Blood Alcohol Concentrations in Adult Rats: A Phenomenon Potentially Related to Gastric Function

In spite of the fact that drinking and smoking often occur together, little is known about the pharmacokinetic interaction between alcohol and nicotine. Previous research in neonatal rats demonstrated that nicotine reduces blood alcohol concentrations (BACs) if alcohol and nicotine are administered simultaneously. However, it is unclear whether such a phenomenon can be observed in adult subjects, given the fact that there is an ontogenetic difference in alcohol metabolism. A range of nicotine doses (0, 0.25, 0.5, 1, 2, 4, and 6 mg/kg) were administered individually with an alcohol dose (4 g/kg) via intragastric (IG) intubation to adult female rats, and the resultant BACs were measured at various time points following drug administration. Furthermore, the hypothesis that nicotine's role in reducing BACs is mediated through factors related to gastric function was examined by comparing the resultant BACs after an IG intubation or intraperitoneal (IP) injection of alcohol. The results from this study showed significant nicotine dose-related decreases in BACs with 0.5, 1, 2, 4, and 6 mg/kg doses of nicotine at the various time points assessed. This effect, however, occurred only when alcohol was administered via IG intubation, but not after an IP injection of alcohol. These results suggest that the nicotine-induced decrease in BAC may be related to gastric function. One possible explanation was related to nicotine's action in delaying gastric emptying. The longer the alcohol was retained in the stomach, the more likely that the alcohol would be metabolized by gastric alcohol dehydrogenase before its absorption into the bloodstream by the small intestine (the major site of alcohol absorption).

The effects of pregnancy on ethanol clearance

We have studied the effects of pregnancy on ethanol clearance rates and on blood and urine ethanol concentrations (BECs and UECs) in adult Sprague–Dawley rats infused with ethanol intragastrically. Pregnant rats had greater ethanol clearance following an intragastric or intravenous ethanol bolus (3 or 0.75 g/kg, respectively) relative to non-pregnant rats ( p < 0.05). Pregnant rats infused with ethanol-containing diets for several days had lower ( p < 0.05) UECs than non-pregnant rats when given the same dose of ethanol. Non-pregnant rats infused ethanol-containing diets at two levels of calories (the higher caloric intake required by pregnant rats [220 kca/kg 75/d] or the normal calories required for non-pregnant rats [187 kcal/kg 75/d]) had statistically equal UECs, suggesting that increased caloric intake was not responsible for the effect of pregnancy. While the activity of hepatic alcohol dehydrogenase (ADH) did not differ with pregnancy, gastric ADH activity was increased ( p < 0.001). Furthermore, total hepatic aldehyde dehydrogenase (ALDH) and hepatic mitrochrondrial protein were increased ( p < 0.05) and hepatic CYP2E1 activity was suppressed ( p < 0.05). The results suggest that pregnancy increases ethanol elimination in pregnant rats by: 1) induction of gastric ADH; 2) elevated hepatic ALDH activity; and 3) increased mitochondrial respiration. The greater ethanol clearance results in lower tissue ethanol concentrations achieved during pregnancy for a given dose, and this may have clinical significance as a mechanism to protect the growing fetus from ethanol toxicity.

Educating women about the hidden dangers of alcohol.

1. There is mounting research evidence that alcohol use and abuse affects women much differently than men. 2. Research indicates that women absorb and metabolize alcohol differently than men, partly due to body composition differences and the production of less gastric alcohol dehydrogenase by women. 3. Women of child-bearing age who engage in binge drinking are at increased risk of bearing children with fetal alcohol syndrome or alcohol-related neurological deficits. 4. Psychiatric nurses are often in the position to provide education and counseling to women regarding the hidden dangers of alcohol use and abuse.

Effects of food on ethanol metabolism.

The goals of the present study were (1) to obtain ethanol pharmacokinetic data from fed dogs, and (2) perform Monte Carlo simulation to determine the effect of food on pharmacokinetic model parameter values. To a cohort of five fed dogs, 1 g ethanol per km body weight was administered as a gavage of 20% w/v ethanol solution. Blood samples taken at 0, 10, 20, 30, 40, 60, 80, 100, 120, 180, 240, and 360 minutes after the dose were mixed with anticoagulant and stored on ice. Blood ethanol concentration was determined via headspace chromatograph. Monte Carlo simulation with an ethanol pharmacokinetic model was used to estimate model parameter values and parameter standard deviations by minimization of the chi-squared function. Results indicate that 50.6 +/- 21.0% of the ethanol dose was absorbed in the stomach, and an insignificant amount of ethanol was metabolized by gastric alcohol dehydrogenase postulated for the model. At 6 hours after the ethanol dose 59.4 +/- 21.0% of the ethanol dose was retained in the dogs' stomachs.

Monte Carlo Simulation of an Ethanol Pharmacokinetic Model

Background One challenge of using even relatively simple pharmacokinetic models is valuation of model parameters. Unknown model parameter values can be determined by fitting the model to measured data. Goals of the present study were to (1) obtain ethanol pharmacokinetic data from a cohort of dogs, (2) propose a physiologic ethanol pharmacokinetic model, (3) and perform Monte Carlo simulation to determine model parameter values. The rationale for the particular model proposed here was to account for the interrelationship between blood ethanol concentration and gastrointestinal physiology. Methods To each of five fasted dogs, 1 g of ethanol/kg body weight was administered as a gavage of 20% w/v ethanol solution. Developed was an ethanol pharmacokinetic model that comprised a gastric emptying mechanism, a body water compartment, ethanol diffusion through the stomach mucosa, gastric alcohol dehydrogenase (GADH) oxidation of ethanol, diffusion through the small intestine epithelia to the villi, a countercurrent exchanger model of the villi, and liver alcohol dehydrogenase oxidation of ethanol. Monte Carlo simulation was used to estimate model parameter values and standard deviations by minimization of the χ2 function. Results Fitting the experimental data to the model using Monte Carlo simulation yielded reasonable values for model parameters. The model predicted that the capacity for ethanol absorption in the intestine was 6.79-fold greater than the ethanol absorption capacity in the stomach. The model indicated that 23.8 ± 8.3% of the ethanol dose was actually absorbed in the stomach, and an insignificant amount of ethanol was metabolized by GADH. Conclusions Ethanol metabolism by GADH is insignificant in the present case. The blood ethanol profile was strongly determined by gastric emptying. Differences between experimental data and simulation results largely result from the gastric emptying model selected. Therefore, accuracy of the complete pharmacokinetic model can be improved significantly by improving the gastric emptying model.

Monte Carlo Simulation of an Ethanol Pharmacokinetic Model

Background One challenge of using even relatively simple pharmacokinetic models is valuation of model parameters. Unknown model parameter values can be determined by fitting the model to measured data. Goals of the present study were to (1) obtain ethanol pharmacokinetic data from a cohort of dogs, (2) propose a physiologic ethanol pharmacokinetic model, (3) and perform Monte Carlo simulation to determine model parameter values. The rationale for the particular model proposed here was to account for the interrelationship between blood ethanol concentration and gastrointestinal physiology.Methods To each of five fasted dogs, 1 g of ethanol/kg body weight was administered as a gavage of 20% w/v ethanol solution. Developed was an ethanol pharmacokinetic model that comprised a gastric emptying mechanism, a body water compartment, ethanol diffusion through the stomach mucosa, gastric alcohol dehydrogenase (GADH) oxidation of ethanol, diffusion through the small intestine epithelia to the villi, a countercurrent exchanger model of the villi, and liver alcohol dehydrogenase oxidation of ethanol. Monte Carlo simulation was used to estimate model parameter values and standard deviations by minimization of the χ2 function.Results Fitting the experimental data to the model using Monte Carlo simulation yielded reasonable values for model parameters. The model predicted that the capacity for ethanol absorption in the intestine was 6.79‐fold greater than the ethanol absorption capacity in the stomach. The model indicated that 23.8 ± 8.3% of the ethanol dose was actually absorbed in the stomach, and an insignificant amount of ethanol was metabolized by GADH.Conclusions Ethanol metabolism by GADH is insignificant in the present case. The blood ethanol profile was strongly determined by gastric emptying. Differences between experimental data and simulation results largely result from the gastric emptying model selected. Therefore, accuracy of the complete pharmacokinetic model can be improved significantly by improving the gastric emptying model.

Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a caucasian population.

The stomach is involved in first-pass metabolism of alcohol in humans. As conflicting data were published regarding the influence of age and gender on the activity of alcohol dehydrogenase (ADH) in human gastric mucosa, the present study aimed at the investigation of these and other potentially confounding factors (alcohol consumption, smoking, drug intake) on its activity in a Caucasian population. ADH activity was assessed in endoscopic gastric biopsy specimens from 111 Caucasian subjects aged 20-80 years, of whom 51 were females. Highest ADH activity was measured at ethanol concentrations between 150 and 500 mM. Mean ADH activity was higher in antral specimens than in those from the gastric corpus of the same subjects. ADH activity decreased with increasing age in males, while the values in females aged 41-60 years were higher than those in women aged 20-40 or 61-80 years. In men aged 20-40 years, consumption of larger quantities of alcohol (>0.8 g/kg body weight/day) was associated with reduced ADH activity. H(2)-Receptor antagonist treatment also decreased gastric ADH activity. The results indicate that ADH activity in human gastric mucosa is negatively associated with consumption of larger quantities of alcohol. The question of whether ADH activity is higher in males or females can only be answered with respect to age. The gastric ADH activity in young men is distinctly higher compared to young women, but the opposite holds true in middle-aged subjects.

Activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes in human gastric mucosa.

The gastric alcohol dehydrogenase (ADH) plays an important role in the "first pass" metabolism of ethanol. Human ADH exists in multiple forms, grouped into six classes and located in different tissues. In present study we investigated the activity of four classes (I, II, III, and IV) of alcohol dehydrogenase isoenzymes in the different parts of stomach (corpus and antrum) in patients with suspected gastric ulcer. The aim of the study was assess the particular role of different classes of ADH in the gastric dehydrogenase activity. For the measurement of the activity of class I and class II isoenzymes, we employed new fluorometric methods with specific substrates. The activity of class III alcohol dehydrogenase was measured by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as a substrate, respectively. All biopsy specimens were taken from less changed areas of the antrum and body of the stomach of 68 patients suspected of having gastric ulcer. It was found that ADH IV (gastric) activity was the highest (14.76 +/- 0.68 in the corpus of the stomach in men; and 7.61 +/- 0.68 in women, respectively). The activity of the ADH III isoenzyme was lower than that of ADH IV. The activities of class I and II ADH isoenzymes were barely detectable. All tested classes of ADH had higher activity in the corpus than in the antrum and in males than in females. In conclusion, the most important form of gastric ADH is isoenzyme of class IV, less important is the isoenzyme of class III. ADH classes I and II seem to have no role in the stomach.

Gender differences in alcohol metabolism. Physiological responses to ethanol.

A gender difference in alcohol pharmacokinetics has been suggested to explain why women are more vulnerable to ethanol's toxic effects. The results of animal experiments suggest that females exhibit higher alcohol metabolic rates than males as a result of hormonal differences. Experimental results examining gender differences in human alcohol metabolism have been inconsistent; the diversity of experimental protocols and variety of pharmacokinetic parameters reported have made comparisons of these studies very difficult. Variability in alcohol metabolic rate between individuals of the same sex is often significant, preventing an assessment of gender differences in some studies. This chapter attempts to summarize the findings of studies from the last decade that examined the role of gender and sex hormone differences on ethanol metabolism in men and women. The role of body composition, genetic factors, gastric and hepatic alcohol dehydrogenase, and gastric absorption in creating gender differences in alcohol metabolism is discussed. Suggestions are offered that may result in better cross-study comparisons and more consistent experimental results.

Pharmacokinetics of ethanol: a review of the methodology

This paper reviews current concepts on tools for studying the pharmacokinetics of alcohol. It has been known that ethanol metabolism occurs mainly in the liver via alcohol dehydrogenase and an accessory microsomal pathway. The contribution of each pathway has been examined by administration of metabolic inhibitors. The role of gastric alcohol dehydrogenase in the first-pass effects of ethanol has been speculative and may be relatively low. Some pharmacokinetic approaches with mathematical models have elucidated the role of gastric alcohol dehydorgenase, hepatic alcohol dehydrogenase and cytochrome P450 2E1 in ethanol elimination. The scale-up of ethanol elimination kinetics has enabled extrapolation from animal models to human kinetics. The clarification of the pharmacokinetics of ethanol is very important for estimating the effects of ethanol on biological events.

Effect of Helicobacter pylori Infection on the Activity of Class I, III and IV Alcohol Dehydrogenase in the Human Stomach

Background/Aims: In the human stomach various alcohol dehydrogenase (ADH) isoenzymes exist. The gastric ADH activity is affected by a number of factors including also the infection of Helicobacterpylori. The objective was to investigate the activity of alcohol dehydrogenaseisoenzymes of class I, III and IV in endoscopic specimens of gastric mucosa from the different parts of the stomach of men and women, considering the H. pylori infection. Method: Biopsy samples of gastric mucosa were taken from the corpus and antrum of 68 patients (42 of men and 26 of women) suspected for gastric ulcer. The colonization of H. pylori was present in 22 samples of men and 13 samples of women. The activity of class I isoenzyme was measured by the fluorimetric method with a specific substrate (4-methoxy-1-naphthaldehyde) and the activity of class III and IV by the photometric method with n-octanol and m-nitrobenzaldehyde as a substrates, respectively. Results: In infected samples from the antrum and corpus of men’s and women’s stomachs the activity of class IV isoenzyme was decreased as compared to non-infected specimens. The activity of class III isoenzyme was decreased in the infected samples from the corpus of male patients, but the activity of class I does not significantly differ between infected and noninfected specimens from both sexes. Conclusion:H. pylori infection leads to significant decrease in the activity of class IV ADH in the stomach of men and women.