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Objective: FOXP3 single nucleotide polymorphisms (SNPs) were recently elucidated to influence the development of preeclampsia (PE), but the results on this issue still remained controversial. Thus, a meta-analysis was implemented to systematically investigate the roles of FOXP3 SNPs in PE., Methods: Eligible publications were identified by retrieving relevant electronic databases. Meanwhile, the association intensity was estimated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) in various genetic models., Results: Totally eight investigations involving 3446 subjects were enrolled in the final meta-analysis. The AC and AC + CC genotypes of FOXP3 rs3761548 were related to the susceptibility of PE in over-dominant (OR = 1.19, 95%CI = 1.02-1.38, P = 0.03) and recessive (OR = 0.59, 95% CI: 0.36-0.97, P = 0.04) models. Furthermore, correlation between rs2232365 and PE was observed in recessive model (GG vs. GA + AA) (OR = 0.79, 95%CI: 0.65-0.97, P = 0.03). Moreover, rs2232365 GA and GG + GA genotypes were associated with the severity of PE. However, rs4824747, rs3761547 and rs2280883 polymorphisms had no significant impact on PE susceptibility., Conclusions: FOXP3 rs3761548 and rs2232365 SNPs influenced the PE susceptibility and therefore may be potential biomarkers for prediction of PE risk., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol in mammals. The steady-state metabolic flux of ethanol has been poorly understood., Methods: We investigated flux rates of the individual steps of ethanol metabolism in perfused rat livers treated with ALDH inactivator cyanamide as an attempt to mimic human ALDH2 deficiency commonly seen in East Asians. The net rates of ethanol oxidation, acetaldehyde oxidation, and acetate activation were determined with a set of defined equations, based on the set influx rates of ethanol and the measured efflux rates of ethanol, acetaldehyde, and acetate., Results: After intraperitoneal injections of 0.2 and 1.5 mg/kg cyanamide, hepatic activities of mitochondrial ALDH2 and cytoplasmic ALDH1A1 decreased to a similar degree, that is, 51 to 57% and 69 to 74%, compared with the corresponding controls, respectively, whereas cytoplasmic ADH1 activity remained unchanged. At infusing 2 mM ethanol, acetaldehyde oxidation rate well matched (99%) the net ethanol oxidation rate in control liver. Both the ethanol and acetaldehyde oxidation rates were significantly decreased after cyanamide treatments. At 10 mM ethanol, the efflux acetaldehyde was significantly higher than that infusing 2 mM ethanol in both control and cyanamide groups. Seventy-eight percent of the oxidized ethanol released as efflux acetate. At 2 mM ethanol, the apparent flux control coefficients of ADH1 were assessed to be 0.78, 0.54, and 0.39, respectively, in control, low, and high cyanamide-treated livers. Kinetic simulations revealed that inhibition by acetaldehyde may largely account for the observed reduction of ADH1 oxidation rates after cyanamide treatment., Conclusions: Our results provide the first flux evidence that ADH and ALDH are steps influencing steady-state metabolism of ethanol in rat livers with inactivated ALDHs., (Copyright © 2015 by the Research Society on Alcoholism.)

Background: It has been well documented that a variant allele of mitochondrial aldehyde dehydrogenase 2 (ALDH2), ALDH2*2, commonly occurs in East Asians but rarely in other ethnic populations. This unique allelic variation significantly influences drinking behavior and susceptibility to development of alcoholism. Previous structural, functional, and cellular studies indicate that the resulting variant polypeptide subunit K (Lys-487) exerts dominance of null activity and shorter half-life over the tetrameric enzyme molecules in distinct manners. However, the in vivo evidence for the proposed dominance mechanisms remains lacking., Methods: To address this question, we investigated 33 surgical liver samples identified to be normal homozygous ALDH2*1/*1 (n = 17), heterozygous ALDH2*1/*2 (n = 13), and variant homozygous ALDH2*2/*2 (n = 3). The ALDH2 activity was determined at a sufficient low acetaldehyde concentration (3 μM) and the isozyme protein amount by immunotitration using purified class-specific antibodies., Results: The tissue ALDH2 activity in heterozygotes was 17% that of the ALDH2*1/*1 genotype (p < 0.001), whereas the activity of ALDH2*2/*2 was too low to be precisely determined. The protein amounts of tissue ALDH2 in variant homozygotes and heterozygotes were similar but only 30 to 40% that of normal homozygotes (p < 0.01). Linear regression analyses show that ALDH2 activities were significantly correlated with the protein contents in normal homozygotes and heterozygotes, respectively (p < 0.005). The specific activity of ALDH2 per enzyme protein in ALDH2*1/*2 was 38% that of ALDH2*1/*1 (p < 0.001)., Conclusions: These results are in good agreement with those predicted by the model studies, thus providing in vivo evidence for differential impairments of hepatic acetaldehyde oxidation with alcohol metabolism in individuals carrying ALDH2*1/*2 and ALDH2*2/*2 genotypes., (Copyright © 2013 by the Research Society on Alcoholism.)

Background: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol (EtOH). Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. This study aimed to systematically determine the functional expressions and cellular localization of ADH and ALDH family members in human small bowel., Methods: One hundred and seventeen surgical specimens of duodenal mucosae, 34 jejunal mucosal specimens, and 14 paired specimens of stomach, duodenum, and jejunum from same individuals were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing, and the ADH/ALDH activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies, and the cellular localizations were detected by immunohistochemistry and histochemistry., Results: The activities of ADH1C*1/*1 allelotype were significantly higher than those of the ADH1C*1/*2 allelotype in duodenum (p < 0.001) and in jejunum (p < 0.05); and the activity of ADH2-expressing phenotype was significantly higher than that of the ADH2-missing phenotype in duodenum (p < 0.05). The activities of ALDH2-inactive phenotype were not significantly different from those of the ALDH2-active phenotype in duodenum and jejunum. Stomach exhibited significantly lower ADH activity (p < 0.05), and duodenum displayed significantly lower ALDH activity (p < 0.001) comparing the paired gastric, duodenal, and jejunal mucosae of same individuals. Gender and age did not significantly influence the ADH and ALDH activities in duodenum. The isozyme protein contents in duodenum and jejunum were in the following decreasing order: ALDH1A1, ADH1/ALDH2, ADH3, ADH2, and ALDH3A1. Villous epithelial cells, cryptic Paneth cells, and Brunner's gland ductal cells revealed a greater immunostaining intensity with ADH1, ALDH1A1, and ALDH2., Conclusions: ADH and ALDH isozymes are differentially expressed in the various cell types of duodenum and jejunum. The results suggest that proximal small intestine can substantively contribute to first-pass metabolism of EtOH under certain conditions and that cytotoxic acetaldehyde and EtOH perturbation of retinol metabolism might play an etiological role in the pathogenesis of small bowel., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are major enzymes responsible for metabolism of ethanol. Genetic polymorphisms of ADH1B, ADH1C, and ALDH2 occur among racial populations. The metabolic effect and metabolites contribute to pathogenesis of pancreatic injury. The goal of this study was to determine the functional expressions and cellular localization of ADH and ALDH families in human pancreas., Methods: Fifty five surgical specimens of normal pancreas as well as 15 samples each for chronic pancreatitis and pancreatic cancer from archival formalin-fixed paraffin-embedded tissue specimens were investigated. Class-specific antibodies were prepared by affinity chromatographies from rabbit antisera raised against recombinant human ADH1C1, ADH4, ADH5, ADH7, ALDH1A1, ALDH2, and ALDH3A1. The isozyme expression patterns of ADH/ALDH were identified by isoelectric focusing, and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting, and the cellular localizations were detected by immunohistochemistry and histochemistry., Results: At 33 mM ethanol, pH 7.5, the activities were significantly different between allelic phenotypes of ADH1B. The activity of ALDH2-inactive phenotypes was slightly lower than ALDH2-active phenotypes at 200 microM acetaldehyde. The protein contents were in the following decreasing order: ALDH1A1, ALDH2, ADH1, and ADH5. ADH1B was detected in the acinar cells and ADH1C in the ductular, islet, and stellate cells. The expression of ADH1C appeared to be increased in the activated pancreatic stellate cells in chronic pancreatitis and pancreatic cancer., Conclusions: Alcohol dehydrogenase and ALDH family members are differentially expressed in the various cell types of pancreas. ADH1C may play an important role in modulation of activation of pancreatic stellate cells.

Background: Alcohol dehydrogenase (ADH) is the principal enzyme responsible for ethanol metabolism in mammals. Human ADH constitutes a unique complex enzyme family with no equivalent counterpart in experimental rodents. This study was undertaken to quantitatively assess relative contributions of human ADH isozymes and allozymes to hepatic versus gastric metabolism of ethanol in the context of the entire family., Methods: Kinetic parameters for ethanol oxidation for recombinant human class I ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, and ADH1C2; class II ADH2; class III ADH3; and class IV ADH4 were determined in 0.1 M sodium phosphate at pH 7.5 over a wide range of substrate concentrations in the presence of 0.5 mM NAD+. The composite numerical formulations for organ steady-state ethanol clearance were established by summing up the kinetic equations of constituent isozymes/allozymes with the assessed contents in livers and gastric mucosae with different genotypes., Results: In ADH1B*1 individuals, ADH1B1 and ADH1C allozymes were found to be the major contributors to hepatic-alcohol clearance; ADH2 made a significant contribution only at high ethanol levels (> 20 mM). ADH1B2 was the major hepatic contributor in ADH1B*2 individuals. ADH1C allozymes were the major contributor at low ethanol (< 2 mM), whereas ADH1B3 the major form at higher levels (> 10 mM) in ADH1B*3 individuals. For gastric mucosal-alcohol clearance, the relative contributions of ADH1C allozymes and ADH4 were converse as ethanol concentration increased. It was assessed that livers with ADH1B*1 may eliminate approximately 95% or more of single-passed ethanol as inflow sinusoidal alcohol reaches approximately 1 mM and that stomachs with different ADH1C genotypes may remove 20% to 30% of single-passed alcohol at the similar level in mucosal cells., Conclusions: This work provides just a model, but a strong one, for quantitative assessments of ethanol metabolism in the human liver and stomach. The results indicate that the hepatic-alcohol clearance of ADH1B*2 individuals is higher than that of the ADH1B*1 and those of the ADH1B*3 versus the ADH1B*1 vary depending on sinusoidal ethanol levels. The maximal capacity for potential alcohol first-pass metabolism in the liver is greater than in the stomach.

The aim of this study was to investigate the relationship between alcohol metabolizing enzyme genotypes and mortality risk of liver diseases among patients with alcohol dependence. A total of 130 male patients with a DSM-III-R diagnosis of alcohol dependence (mean age 40+/-10 years) were recruited consecutively to the study from 1994 to 1995. Blood biochemistry and hepatitis B viral surface antigen (HBsAg) were measured. The genotypes of ADH2, ADH3 and ALDH2 were determined by polymerase chain reaction and restriction fragment-length polymorphism. The mortality cases were identified by matching data files of the death certification system of the National Department of Health issued from 1994 to 2001. Mortality analysis revealed that 58 of 130 cases (45%) died during the follow-up period. Among them, 21 cases died of liver diseases. Mortality was not higher in HBsAg positive than in negative subjects. The genotypes of alcohol metabolizing enzymes are not associated with the mortality risk of liver diseases. The small sample size was a limitation of this study. How functional genetic polymorphism of the alcohol metabolizing enzymes causes liver damage is still not clear. Continuous study of this topic is necessary.

Background: The role of the dopamine D2 receptor (DRD2) gene in the development of alcohol abuse or dependence is controversial. The controversy is due in part to the disparate definitions pertaining to the control groups used and to the definitions of subtypes in alcohol dependence. In the Han Chinese population, the alcohol dehydrogenase 1B*2/*2 (ADH1B*2/*2) genotype and the aldehyde dehydrogenase 2*2 (ALDH2*2) allele have been considered as protective factors against alcohol abuse or dependence. Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism. We hypothesized that the ADH1B and ALDH2 genes might interact with the DRD2 gene and that the association between the DRD2 gene and alcohol dependence might be affected by different ADH1B and ALDH2 genotypes. This study examined whether the DRD2 gene is associated with specific subtypes of alcohol dependence and evaluated the relationship between the DRD2 gene and alcohol-metabolizing genes in a specific subtype of alcohol dependence., Methods: Of the 465 Han Chinese subjects who were recruited for the study, 71 were classified with pure alcohol dependence, 113 with both alcohol dependence and anxiety-depression (ANX/DEP ALC), and 129 with anxiety-depression but without alcohol dependence (ANX/DEP). The remaining 152 subjects were supernormal controls. All subjects were interviewed with the Chinese version of the modified Schedule of Affective Disorders and Schizophrenia-Lifetime; all alcohol dependence, anxiety, and major depressive diagnoses were made according to DSM-IV criteria., Results: The DRD2 gene was not found to be associated with pure alcohol dependence or ANX/DEP, but was found to be associated with ANX/DEP ALC. Furthermore, the association between the DRD2 gene and ANX/DEP ALC was shown to be under the control of the ALDH2*1/*1 and ADH1B*1/*2 genotypes., Conclusions: ANX/DEP ALC is a specific subtype of alcohol dependence. Because ANX/DEP ALC was associated with the DRD2 gene only under the stratification of ADH1B*1/*2 or ALDH2*1/*1, the DRD2 gene might interact with the ADH1B gene and the ALDH2 gene, respectively, in the development of ANX/DEP ALC in the Taiwan Han Chinese population.

Background: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for ethanol metabolism in humans. The stomach is involved in the metabolism of alcohol during absorption. Conflicting reports exist with regard to the influence of sex and age on the activity of ADH in the human gastric mucosa. The purpose of the present study was to determine the effects of age and sex on the expression pattern and activities of stomach ADH and ALDH., Methods: A total of 115 endoscopic gastric biopsy specimens were investigated from Han Chinese men (n = 70) and women (n = 45) aged 20-79 years with approximately even distribution among 10-year age intervals. The expression patterns of ADH and ALDH were identified by isoelectric focusing, and the activities were assayed spectrophotometrically., Results: The expression patterns of gastric ADH and ALDH remained unchanged with respect to sex and age. At 33 mM or 500 mM ethanol, pH 7.5, the ADH activities did not differ significantly among the various age groups or between men and women. At 200 microM or 20 mM acetaldehyde, the ALDH activities did not differ significantly in relation to sex and age. No correlations were found between the ADH or ALDH activities at both the high and low substrate concentrations and the ages in men and women., Conclusions: The results indicate that there is no significant effect of either sex or age on the expression pattern and activity of ADH and ALDH in the human gastric mucosa. The stomach ADH seems unlikely to account for possible variations in the first-pass metabolism of alcohol with regard to sex and age.

Background: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism., Methods: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography., Results: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals., Conclusions: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.

Background: Recent studies on the genetics of alcoholism have examined the association between alcoholism and the dopamine D2 receptor locus (DRD2); our study of Chinese Han gave negative results (Lu et al., 1996). The different genotypes at the genes encoding the enzymes involved in alcohol metabolism, class one alcohol dehydrogenase (ADH2 and ADH3) and mitochondrial aldehyde dehydrogenase (ALDH2), have previously been shown to confer different predispositions to the development of alcoholism in Chinese Han males (Thomasson et al., 1991; Chen WJ et al., 1996; Chen CC et al., unpublished data). Therefore, association studies of alcoholism in Chinese Han might be more sensitive if controlled for the genotypes of ADH2,ADH3, and ALDH2, when other loci, such as DRD2, are examined. This study employs such controls to evaluate the evidence for an association between alcoholism and TaqI-A and TaqI-B genotypes and haplotypes at DRD2 in the Chinese Han population., Methods: We studied 213 Chinese Han subjects (128 alcoholics and 85 nonalcoholics) with alcohol dependence defined according to DSM-III-R criteria., Results: Significant linkage disequilibrium was observed between the TaqI-A and TaqI-B sites at the DRD2 locus, as previously seen in smaller samples, but no significant association was observed between these genetic variants at the DRD2 locus and alcoholism in Chinese Han. Several different stratifications by ADH and ALDH2 genotypes were examined; no genotypes or haplotypes at DRD2 differ between alcoholics and nonalcoholics except for a small number of nominally significant p-values which do not constitute significant results given the many tests done, some of which are not independent of one another due to linkage disequilibrium. These tests included considering the high risk (ADH2*1/*1; *1/*2; ADH3*1/*2; *2/*2; and ALDH2*1/*1) and the low risk (ADH2*2/*2; ADH3*1/*1; and ALDH2*1/*2; *2/*2) groups of alcoholics, as well as nonalcoholic controls., Conclusions: After stratification by the relevant genotypes of ADH2, ADH3, and ALDH2 no significant association exists between the genetic variants at the DRD2 locus and alcoholism in the Chinese Han population.

Genetic factors may play a role in the development of alcoholic liver disease (ALD). Cytochrome P4502E1 (CYP2E1) catalyzes the oxidation of ethanol, producing acetaldehyde and free radicals capable of reacting with and peroxidizing cell membranes. Polymorphisms have been identified in the 5-flanking region of the CYP2E1 gene that may alter the transcriptional activity. In our laboratory, no difference in c1 and c2 allele frequencies was observed between alcoholic patients with or without liver disease in Caucasian men, but there is reported data to the contrary for other populations. To determine if there is a differential susceptibility to ALD between ethnic groups that differ in the frequency of the c2 allele, we studied 30 Han Chinese with severe alcoholic liver disease. Allele frequencies of alcoholics with cirrhosis were compared with 46 alcoholic and 100 nonalcoholic Han individuals without liver disease. To identify the type A (homozygous for c1), type B (heterozygous for c1 and c2) and type C (homozygous for c2) genotypes, DNA encompassing the polymorphisms was amplified by polymerase chain reaction, slot-blotted, and probed with allele-specific oligonucleotides, No significant differences in c2 allele frequencies were found: 0.23 for alcoholics with severe liver disease, 0.20 for alcoholics without liver disease, and 0.26 for the normal population. There also was no difference in c2 allele frequencies between alcoholic and nonalcoholic Atayal natives from Taiwan. Therefore, our results suggest that the allelic variations at the CYP2E1 gene locus also do not significantly affect the development of alcoholism or ALD in Han Chinese and Atayal natives of Taiwan.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isoenzyme patterns from 69 (men, 47; women, 22) surgical colon mucosal specimens were identified by agarose isoelectric focusing. gamma-ADH was found to be the predominant form in the mucosa, whereas only beta-ADH was detectable in the muscle layer. ALDH1, ALDH2, and ALDH3 were detectable in the mucosa, with cytosolic ALDH1 being the major form. At pH 7.5, the ADH activities in the colon mucosae with the homozygous phenotype (exhibiting gamma 1 gamma 1) and the heterozygous phenotype (exhibiting gamma 1 gamma 1, gamma 1, gamma 2, gamma 2, gamma 2) were determined to be 183 +/- 13 and 156 +/- 30 nmol/min/g tissue, respectively. The ALDH activities in the ALDH2-active and ALDH2-inactive phenotypes were determined to be 40.2 +/- 2.3 and 34.6 +/- 2.0 nmol/min/g tissue, respectively. The lack of significant difference in the ALDH activities between these two phenotypic groups can be attributed to the very low expression of the mitochondrial ALDH2 in the colon mucosa. No significant differences in the ADH or the ALDH activities were found between the men and women studied and between the three age groups (20-40, 49-70, and 72-83 years). The ascending, transverse, descending, and sigmoid colons exhibited similar ADH and ALDH activities. The isoenzyme patterns of ADH and ALDH remained unaltered in colon carcinomas, except that a significant reduction of the enzyme activities was found in the cancer tissue as compared with the adjacent normal portions. it is concluded that human colon mucosa exhibits significant amounts of ethanol- and acetaldehyde-oxidizing activities.

Genetic variation at two polymorphic alcohol dehydrogenase loci, ADH2 and ADH3, and at the polymorphic mitochondrial aldehyde dehydrogenase locus, ALDH2, may influence the risk of developing alcoholism by modulating the rate of elimination of ethanol and the rate of formation and elimination of acetaldehyde. Populations differ in allele frequencies at these loci. We determined the genotypes at all three of these loci in Atayal natives of Taiwan. The frequencies of ADH2*2, ADH3*1, and ALDH2*1 alleles (0.91, 0.99, and 0.95, respectively) were significantly higher among the Atayal than among a predominantly Han Chinese population from Taiwan. Among the Atayal, the group with alcohol use disorders (alcohol dependence and alcohol abuse) had a significantly lower frequency of the ADH2*2 allele (0.82) than those without alcohol use disorders (0.91). The ADH2*2 allele encodes the beta 2 subunit; isozymes containing beta 2 subunits oxidize alcohol faster in vitro than the beta 1 beta 1 isozyme encoded by ADH2*1. Thus, the simplest explanation for these data is that individuals with a beta 2 isozymes have a higher rate of ethanol oxidation, which is a deterrent to alcohol abuse and dependence in some individuals. The Atayal with alcohol use disorders also had a lower frequency of ALDH2*2 than the controls; this allele is known to be responsible for the alcohol-flush reaction among Asians, and thereby deters drinking.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isoenzymes from surgical esophageal and gastric mucosa were compared by agarose isoelectric focusing. Two prominent ADH forms, designated mu 1 (equivalent to the recently reported mu-form) and mu 2, were expressed in all the 15 esophagus specimens studied, whereas only four of seven examined gastric specimens exhibited a weak to moderately strong mu 1-ADH activity band on the isoelectric focusing gels. pI values of the esophageal mu 1-ADH and mu 2-ADH, and the liver pi-ADH were determined to be 8.61, 8.13, and 8.90, respectively. mu-ADHs exhibited high Km for ethanol (12 mM) and low sensitivity to 4-methylpyrazole inhibition. ALDH3 (BB form) and ALDH1 were the major high- and low-Km aldehyde dehydrogenase in the esophagus, respectively. The ADH and ALDH activities were determined at pH 7.5 to be 751 +/- 78 and 29.9 +/- 3.0 nmol/min/g tissue, respectively (measured at 500 mM ethanol or at 200 microM acetaldehyde; mean +/- SEM; N = 15). The esophageal ADH activity was approximately 4-fold and the ALDH activity 20% that of the stomach enzyme. Because the presence of high activity and high Km mu-ADHs as well as low-activity ALDH1 were found in human esophageal mucosa, it is suggested that there may exist an accumulation of intracellular acetaldehyde during alcohol ingestion. This reactive and toxic metabolite may be involved in the pathogenesis of alcohol-induced esophageal disorders.