Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele

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.     

Characteristics of Japanese Alcoholics with the Atypical Aldehyde Dehydrogenase 2*2.I. A Comparison of the Genotypes of ALDH2, ADH2, ADH3, and Cytochrome P-4502E1 Between Alcoholics and Nonalcoholics

We examined the genotypes of the aldehyde dehydrogenase (ALDH)-2 , alcohol dehydrogenase (ADH)-2, ADH3 , and P-4502E1 loci of 53 alcoholics and 97 nonalcoholics. All of the subjects fulfilled the DSM-III-R criteria for alcohol dependence. The control group consisted of 97 subjects who were either hospital staff or students. We also compared the frequencies of homozygous ALDH2*1/1 and heterozygous ALDH2*1/2 genotypes in alcoholics. Our study revealed differences in the allelic frequencies of the ALDH2, ADH2 , and ADH3 loci between alcoholics and nonalcoholics. For alcoholics with both homozygous ALDH2*1/1 and heterozygous ALDH2*1/2 genotypes, it was found that ADH2 and ADH3 played important roles. Alcoholics with the heterozygous ALDH2*1/2 genotype showed a significantly higher frequency of ADH2*1/1 than ones with the homozygous ALDH2*1/1 genotype. We assume ADH2*1 plays an important role in the development of alcoholism in alcoholics with the heterozygous ALDH2*1/2 genotype.     

No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan

BACKGROUND: suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism. The ADH1B*2 and ALDH2*2 alleles had been thought to be protective against alcoholism. Recent studies have suggested that either physiological tolerance of blood acetaldehyde, or innate insensitivity to it, or both may play a crucial role in keeping alcoholism from developing by protecting against adverse reactions. ALDH inactive form resulting from ALDH2*2, which slows the elimination of acetaldehyde and the more active isozymes produced by ADH1B*2, could generate higher acetaldehyde levels and thus deter heavy drinking (). The genotype frequency of ADH1B*2/*2 and ALDH2*(1/*2 or 2/*2), which are regarded protective against drinking behavior, is about 70% and 50%, respectively, among the Han Chinese population in Taiwan (Chen et al., 1999a). Most previous studies, however, have failed to separate the effects of antisocial personality disorder from those of alcoholism because of their high comorbidity. To understand the relationship among alcoholism, antisocial personality disorder, and the protective effects of ADH and ALDH, it is necessary to recruit individuals with antisocial personality disorder but without alcoholism. This study was designed to stratify subjects by various ADH1B and ALDH2 genotypes for a more effective association study. The strata were: antisocial alcoholics, antisocial non-alcoholics, community alcoholics, and normal controls. METHODS: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder. RESULTS: We found no difference of ADH1B*2 allele frequency between the subjects of antisocial alcoholism and subjects of antisocial non-alcoholism, but we found significant difference of ALDH2*2 allele between these two groups. CONCLUSIONS: We concluded that there is no alcoholism-protection effect of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan.     

No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population

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.     

Association of the ADH2 genotypes with skin responses after ethanol exposure in Japanese male university students

BACKGROUND: A contribution of the alcohol dehydrogenase-2 (ADH2) polymorphism to alcohol sensitivity and alcohol drinking behavior is still controversial. In this study, we examined the effects of the ADH2 genotypes on skin reactions to ethanol and habitual alcohol intake among Japanese male university students, controlling for the effects of the low Km aldehyde dehydrogenase (ALDH2) genotype, as an extension of our previous study. METHODS: The study subjects were 357 Japanese male students [average age (mean +/- SD) was 23.7 +/- 3.0 years] in a medical university. The subjects completed a questionnaire regarding self-reported alcohol-associated symptoms and alcohol-drinking behavior. The ADH2 and ALDH2 genotypes were determined through digestion of polymerase chain reaction products by restriction enzymes. All subjects participated in the ethanol patch test. We observed skin responses at 0, 5, 15, and 20 min after removal of the tape. RESULTS: Among the ALDH2*1/*1 genotypes, only some subjects with ADH2*1/*2 or ADH2*2/*2 exhibited a positive response, which increased with increasing time after the removal. However, none of comparisons between the different ADH2 genotypes reached statistical significance. Among the ALDH2*1/*2 genotypes, those with ADH2*1/*2 or ADH2*2/*2 showed a significant increase in response with increasing time after the removal and revealed a significantly higher positivity rate at 15 min than those with ADH2*1/*1. In those with the ALDH2*1/*2 genotype, the positive rate of facial flushing with one glass of beer was higher in those with ADH2*1/*2 and ADH2*2/*2 than those with ADH2*1/*1, although this was not significant. However, the ADH2 genotype did not seem to influence drinking frequency or amounts of alcohol intake in each ALDH2 genotype. CONCLUSIONS: This study finds further evidence for a contribution of the ADH2 polymorphism to skin reactions after either local or systemic ethanol exposure in Asian people. However, the effects of the ADH2 polymorphism may be mild because this polymorphism does not seem to influence alcohol drinking behavior in these study subjects.     

Alcohol-metabolizing enzyme gene polymorphisms and alcohol chronic pancreatitis among Polish individuals

Background and aims. Chronic pancreatitis develops in 5–10% of alcohol addicts. In developed societies, alcohol is the cause of chronic pancreatitis in at least 70–80% of cases. The genetic polymorphism of enzymes involved in alcohol metabolism is relevant in the etiopathogenesis of chronic pancreatitis. The aim of the study was to find the ADH, ALDH2 and CYP2E1 alleles and genotypes in the Polish population that are likely to be responsible for higher susceptibility to chronic alcohol pancreatitis. Material and methods. We determined the allele and genotype of ADH2, ADH3, ALDH2 and CYP2E1 in 141 subjects: 44 with alcohol chronic pancreatitis (ACP), 43 healthy alcoholics and 54 healthy non-drinkers as the controls. Genotyping was performed using PCR-RELP methods on white cell DNA. Results. ADH2*1, ADH3*1 alleles and ADH2*1/*1, ADH3*1/*1 genotypes were statistically more frequent among the patients with ACP than among the controls. The ADH3*2/*2 genotype was more frequent among “healthy alcoholics” and in the controls than among those with ACP. In the studied group, only the ALDH2*1 allele was detected, all patients were ALDH2*1/*1 homozygotic. Differences in the CYP2E1 allele and genotype distribution in the examined groups were not significant. Conclusion. In the Polish population examined, ADH3*1 and ADH2*1 alleles may be risk factors for the development of alcoholism. The ADH3*2/*2 genotype may confer protection against ACP. CYP2E1 gene polymorphism is not related to alcoholism and ACP. The Polish population examined is ALDH2*1/*1 homozygotic.     

Polymorphism of ADH and ALDH Genes among Four Ethnic Groups in China and Effects upon the Risk for Alcoholism

The alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) that metabolize ethanol are polymorphic. Different alleles encode subunits of the enzymes that differ in their rate of metabolizing ethanol. These polymorphisms are distributed differently among populations and have been shown to influence the risk for alcoholism in some Asian populations. We have examined the allele frequencies at the ADH2, ADH3 , and ALDH2 loci in four populations from China (Han, Mongolian, Korean, and Elunchun) and in alcoholics within each population. The four populations differ in allele frequencies, with the Elunchun having a much lower frequency of ADH2 *2 alleles, and the Mongolian and Elunchun having a much lower frequency of ALDH2 *2 alleles. Within each population, alleles at one or more of these three loci are protective against alcoholism, although the populations differ in which loci play significant roles. The protective allele at each locus ( ALDH2 * 2 , ADH2 * 2 , and ADH3 * 1 ) encodes a subunit that either metabolizes ethanol to acetaldehyde more rapidly or slows the conversion of acetaldehyde to acetate. Taken as a whole, data demonstrate that genetic differences in the enzymes that metabolize alcohol can substantially affect the risk for alcoholism.     

Accumulation of hemoglobin-associated acetaldehyde with habitual alcohol drinking in the atypical ALDH2 genotype

BACKGROUND: Those with the atypical genotypes of low Km aldehyde dehydrogenase (ALDH2) have high blood concentrations of free acetaldehyde, an active metabolite of ethanol, after drinking alcohol. In the present study, we measured acetaldehyde reversibly bound to hemoglobin (HbAA) in Japanese male workers. METHODS: One hundred and sixty Japanese male workers in one plant participated with informed consent. The subjects were genotyped for the ALDH2 polymorphism by polymerase chain reaction method. HbAA levels were measured using a high performance liquid chromatography system with a fluorescence detector. For the study in which we examined accumulation of HbAA, eight Asian male volunteers participated with informed consent. RESULTS: Although HbAA levels were significantly correlated with recent alcohol consumption in both typical (ALDH2*1/*1) and atypical (ALDH2*1/*2) genotypes, the slope in ALDH2*1/*2 was significantly steeper than that in ALDH2*1/*1. Multiple regression analysis on relevant factors for HbAA revealed that not only recent but also daily alcohol consumption increased HbAA levels in those with the ALDH2*1/*2 genotype, which suggests that HbAA accumulates with habitual drinking. We measured HbAA levels before, during, and after alcohol consumption--one drink (0.4 ml/kg) per day--for 7 consecutive days in male volunteers. During the drinking period, HbAA linearly increased in ALDH2*1/*2 (n = 4) but not in ALDH2*1/*1 (n = 4). After reaching peak levels (+76.1 nmol/g hemoglobin) following the seventh drink, HbAA levels gradually decreased but were significantly higher for 3 days after drinking was discontinued. CONCLUSIONS: We demonstrated that HbAA levels accumulate with habitual alcohol drinking in the atypical ALDH2 genotype. HbAA was shown to be a good biomarker for increased internal exposure levels to acetaldehyde.     

Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals

OBJECTIVE: To investigate the effects of ADH and ALDH gene polymorphism on the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. MATERIAL AND METHODS: We determined the allele and genotype of ADH2, ADH3 and ALDH2 in 198 subjects: 57 with alcohol cirrhosis, 44 with alcohol chronic pancreatitis and 43 "healthy alcoholics"; 54 healthy non-drinkers served as controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on white cell DNA. RESULTS: In the population examined the ADH2*1 allele frequency was 97.97%.The tests did not show the ADH2*3 allele. The ADH3*1 allele frequency was 57.07%. The ADH2*1 and the ADH3*1 alleles were statistically more common among patients who abuse alcohol in comparison with the controls. The ADH2*2 allele was not detected in any of the patients with chronic alcohol pancreatitis. The ADH2*1/*1 and the ADH3*1/*1 genotypes were statistically significantly more common among the patients who abuse alcohol than in the control group. All patients were ALDH2*1/*1 homozygotic. Patients with the ADH3*1 allele and the ADH3*1/*1 genotype started to abuse alcohol significantly earlier in comparison to the patients with the ADH3*2 allele and the ADH3*2 /*2 genotype. CONCLUSIONS: In the Polish population examined, the ADH3*1 allele and the ADH3*1/*1 genotype are conducive to the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis. However, the ADH2*2 allele is likely to protect against these conditions. Genetic polymorphism of ALDH2 shows no correlation with alcohol addiction or alcohol cirrhosis and alcohol chronic pancreatitis. The ADH3*1 allele and the ADH3*1/*1 genotype are conducive to alcohol abuse starting at a younger age.     

Alcohol-Metabolizing Enzyme Polymorphisms and Alcoholism in Japan

The liver enzymes, alcohol dehydrogenase (ADH) and aldehyde de-hydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. Cytochrome P450IIE1 , an ethanol-inducible isozyme of liver microsomal P450 , is also important in ethanol metabolism. Genetic polymorphisms in the 5'-flanking region of the human cytochrome P450IIE1 gene have recently been reported. We hypothesized that the polymorphisms of ADH , ALDH , and P450IIE1 modify the susceptibility to development of alcoholism. We determined the genotypes of the ADH2 , ALDH2 , and P450IIE1 loci of 96 Japanese alcoholics and 60 healthy male subjects, using leukocyte DNA by the restriction fragment-length polymorphism by polymerase chain reaction. The alcoholics had significantly higher frequencies of the ADH2 ¹ and ALDH2 ¹ alleles than did the healthy subjects. No significant difference in the frequency of the P45011E1 genotype was observed between the alcoholics and the healthy subjects. In conclusion, genetic polymorphisms of the ADH and ALDH genes, but not of the P45011E1 gene, influence the risk of developing alcoholism in Japanese.     

Salivary acetaldehyde concentration according to alcoholic beverage consumed and aldehyde dehydrogenase-2 genotype

Background: Acetaldehyde is suspected of playing a critical role in cancer development in the upper aerodigestive tract (UADT). The high salivary acetaldehyde levels after alcohol drinking are partly due to acetaldehyde production by oral bacteria. Some alcoholic beverages, especially Calvados and shochu, contain very high levels of acetaldehyde. Inactive heterozygous aldehyde dehydrogenase‐2 (ALDH2) increases the risk of UADT cancer in drinkers. Methods: In a randomized cross‐over design study, 19 healthy Japanese volunteers ingested 0.6 g ethanol/kg body weight in the form of 13% ethanol Calvados, 13% ethanol shochu, 13% ethanol red wine, and 5% ethanol beer under the fasting conditions at 3‐week intervals. We monitored blood and salivary acetaldehyde concentrations immediately after drinking, and 30, 60, 90, 120, and 180 minutes after completion of drinking. Results: The acetaldehyde concentration of each beverage was: Calvados 0.60 mM (1.86 mM in 40% undiluted solution), shochu 0.60 mM (1.16 mM in 25% undiluted solution), red wine 0.25 mM, and beer 0.14 mM. The salivary acetaldehyde concentration immediately after drinking wine was significantly lower than the other beverages, and it was significantly lower immediately after drinking beer than Calvados. The acetaldehyde concentrations 30 to 180 minutes after drinking were unrelated to the beverage type. Throughout the observation period the salivary acetaldehyde concentrations were much higher than the blood acetaldehyde concentrations in all 12 active ALDH2 homozygotes (24 to 53 μM in saliva vs. 2 to 5 μM in blood) and in all 7 inactive ALDH2 heterozygotes (37 to 76 μM in saliva vs. 12 to 25 μM in blood), and they were 13 to 25 μM higher in the ALDH2 heterozygotes than in the ALDH2 homozygotes after adjusting for age, body weight, sex, smoking and drinking habits, and time since the last toothbrushing. The values after subtracting the blood acetaldehyde concentration from the salivary acetaldehyde concentration were also higher in the ALDH2 heterozygotes than in the ALDH2 homozygotes. Conclusions: There are differences in exposure of the UADT to high salivary acetaldehyde concentrations according to the type of alcoholic beverage and ALDH2 genotype, and the differences partly explain the differences in the cancer susceptibility of the UADT according to alcoholic beverage and ALDH2 genotype.     

Alcohol and aldehyde dehydrogenase genotypes in Korsakoff syndrome

BACKGROUND: Previous studies have suggested a genetic predisposition to the development of Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric syndrome commonly associated with alcoholism; however, little is known about this genetic risk factor. METHODS: To test the hypothesis that altered alcohol or aldehyde regulation is related to the development of WKS, the genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-2 (ADH2) were examined in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic subjects without any WKS symptoms and 175 nonalcoholic controls. RESULTS: Although the frequencies of the ALDH2 genotypes and alleles did not differ significantly between alcoholic subjects with WKS and alcoholics without WKS, the ADH2*1/2*1 genotype and ADH2*1 allele were significantly increased in WKS. CONCLUSIONS: These findings suggest that the ADH2*1/2*1 genotype is a risk factor for the development of WKS in alcoholic patients.     

Gender differences in the effects of ADH1B and ALDH2 polymorphisms on alcoholism

Background: Gender differences are known to exist in the prevalence, characteristics, and course of alcohol dependence. Elucidating gender differences in the characteristics of alcohol dependence is important in gender‐based medicine and may improve treatment outcomes. Many studies have shown that genetic factors are associated with the risk of alcohol dependence in both genders. Polymorphisms of alcohol dehydrogenase‐1B (ADH1B) and aldehyde dehydrogenase‐2 (ALDH2) are strong genetic determinants of alcohol dependence. This study aimed to clarify gender differences in the effects of ADH1B and ALDH2 polymorphism on the development of alcohol dependence. Methods: Subjects were 200 female alcoholics and 415 male alcoholics hospitalized in Kurihama Alcoholism Center. Clinical information and background data were obtained by chart review. ALDH2 and ADH1B genotyping was performed by the polymerase chain reaction–restriction fragment length polymorphism method. Results: The onset age of female alcoholics with inactive ALDH2 genotype was significantly lower than those with active ALDH2 genotype, but the onset age did not differ between the inactive and active ALDH2 group in male alcoholics. The difference in onset age between the ADH1B genotype groups did not reach significant levels. The prevalence of comorbid psychiatric disorders, including major depression, eating disorder, panic disorder, and borderline personality disorder, was significantly higher in female alcoholics with inactive ALDH2 or superactive ADH1B than in those with active ALDH2 or normal ADH1B. Conclusions: ALDH2 polymorphism appears to have contrasting effects on the development of alcoholism in women and men. One possible reason for this gender difference may be the high prevalence of psychiatric comorbidities in female alcoholics with inactive ALDH2.     

Self-Reported Flushing and Genotypes of ALDH2, ADH2, and ADH3 among Taiwanese Han

The aims of this study are to investigate whether self-reported facial flushing postalcohol consumption (PAC) among subjects with ALDH2*1/*1 can be attributed to ADH2 or ADH3 and whether the prediction of ALDH2 genotype can be improved by examining the combination of flushing and other accompanying reactions of PAC sensitivity. Fifty-eight subjects of Han ancestry in Taiwan were interviewed for alcohol-sensitivity reactions and their blood samples were genotyped for ALDH2, ADH2, and ADH3. For subjects with ALDH2*1/*1 ( n = 46), 70% reported to have no flushing PAC and 30% reported flushing PAC. When subjects with ALDH2*1/*1 had ADH2*1/*1 ( n = 11), all reported to have no flushing; otherwise, 35% (for ADH2*1/*2, n = 17) and 44% (for ADH2*2/*2, n = 18) reported flushing. For subjects with ALDH2*1/*1 and at least one ADH2*2 allele, the genotype of ADH3 was not associated with self-reported flushing. PAC flushers with ALDH2M/M (50%) were more likely to report nausea than those with ALDH2*1/*2 (8%). The probability of ALDH2*1/*1 given flushing reported was 0.29, while the probability of ALDH2*1/*1 given both flushing and nausea reported was 0.71. The results indicate that self-reported flushing is determined by both ALDH2 and ADH2 and that prediction of ALDH2 genotype on the basis of self-reported flushing and nausea can help identify subjects at increased risk for alcoholism.     

High incidence of ADH2*1/ALDH2*1 genes among Japanese alcohol dependents and patients with alcoholic liver disease

In an attempt to clarify the genetic factors in alcoholism among the Japanese, polymorphism of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes has been investigated. Genetic polymorphism of ADH2/ALDH2 in 66 cases of normal subjects, 90 cases of alcohol dependent, and 31 patients with alcoholic liver disease among Japanese has been analyzed using a polymerase chain reaction assay followed by a direct sequencing method, because ethanol is mainly catabolized by ADH and ALDH and less by cytochrome P450IIE1 and catalase. The incidence of both ADH2*1/*1 and ALDH2*1/*1 was significantly higher in patients with alcohol dependence and in patients with alcoholic liver disease when compared with that in control subjects. In addition, the incidence of ALDH2*1/*2 and ALDH2*2/*2 was significantly reduced in alcoholics compared with control subjects. Genetic polymorphism of ADH2/ALDH2 in patients with alcoholic liver disease was not different from that of alcohol dependents. According to these results, not only ALDH2 gene, often claimed to be responsible for alcohol dependence among Japanese, but also ADH2 gene polymorphism, which modulates the metabolism of ethanol, play important roles in habitual alcohol intake behavior in Japanese patients and in some patients leads to alcoholic liver diseases. (Hepatology 1996 Feb;23(2):234-9)     

Acetaldehyde Burst Protection of ADH1B*2 Against Alcoholism: An Additional Hormesis Protection Against Esophageal Cancers Following Alcohol Consumption?

This account of recent work presented at the 4th International Symposium on Alcohol Pancreatitis and Cirrhosis reports animal studies aimed at determining the role of the "acetaldehyde burst," generated shortly upon ethanol intake, as the mechanism of protection against alcoholism conferred by the ADH1B*2 polymorphism. Literature studies discussed suggest an additional role of the acetaldehyde burst on the paradoxical (hormesis) protection of the ADH1B*2 polymorphism against esophageal cancers in alcoholics.     

Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics

BACKGROUND: Studies have consistently demonstrated that inactive aldehyde dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described. METHODS: To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass of beer. RESULTS: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/ 2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. CONCLUSION: Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further investigation.     

Relevance of Both Daily Hassles and the ALDH2 Genotype to Problem Drinking among Japanese Male Workers

The effects of genetic polymorphisms in the ALDH2 and ADH2 genes and stress levels, as assessed by the daily hassles scale on the prevalence of problem drinkers, were investigated in males in a Japanese occupational population. The frequency of problem drinkers was estimated by the Kurihama Alcoholism Screening Test (KAST). The prevalence of those with a high KAST score (≥0.0) was significantly higher in ALDH2*1/*1 (18.4%) than in ALDH2*1/*2 (4.8%). Multiple logistic regression analysis revealed significant contributions by levels of alcohol consumption, the ALDH2 genotype, and daily hassles to the prevalence of those with a high KAST score. When we analyzed the data for each ALDH2 genotype, heavier alcohol consumption (≥28.8 ml/day), older age (≥40 years old), and very high daily hassles levels (≥20) significantly increased the prevalence of problem drinkers in ALDH2*1/*1. On the contrary, no variables other than heavier alcohol consumption influenced the prevalence in ALDH2*1/*2. In summary, the present study revealed significant contributions of both daily hassles and the ALDH2 genotype to the increase of problem drinkers in an occupational population. Health promotion activities to prevent from alcohol dependence should focus on ALDH2*1/*1 , especially those of middle age, and should include stress management as a part of their activities.     

4-Methylpyrazole Decreases Salivary Acetaldehyde Levels in ALDH2-Deficient Subjects but Not in Subjects With Normal ALDH2

BACKGROUND: Carcinogenic acetaldehyde is produced from ethanol locally in the upper digestive tract via alcohol dehydrogenases (ADHs) of oral microbes, mucosal cells, and salivary glands. Acetaldehyde is further oxidized into less harmful acetate mainly by the aldehyde dehydrogenase-2 (ALDH2) enzyme. ALDH2-deficiency increases salivary acetaldehyde levels and the risk for upper digestive tract cancer in heavy alcohol drinkers. 4-methylpyrazole (4-MP) is an ADH-inhibitor which could reduce the local production of acetaldehyde from ethanol in the saliva. METHODS: Five ALDH2-deficient subjects and six subjects with normal ALDH2 ingested a moderate dose of alcohol (0.4 g/kg of body weight), whereafter their salivary acetaldehyde levels, heart rate, skin temperature, and blood pressure were followed for up to four hours. Blood acetaldehyde and ethanol levels were determined at 60 min. The experiment was repeated after a week. Two hours before the second study day, the volunteers received 4-MP, 10-15 mg/kg of body weight orally. RESULTS: Total ethanol elimination rate decreased with 4-MP by 38-46% in all subjects. 4-MP also reduced blood acetaldehyde levels and suppressed the cardiocirculatory responses of the ALDH2-deficient volunteers. In addition, salivary acetaldehyde production in ALDH2-deficient subjects was significantly reduced when correlated with salivary ethanol levels. On the contrary, 4-MP did not have any effect on salivary or blood acetaldehyde levels in subjects with normal ALDH2. CONCLUSIONS: A single dose of 4-MP before ethanol ingestion reduces ethanol elimination rate, the flushing reaction, and both blood and salivary acetaldehyde levels in ALDH2-deficient subjects but not in subjects with the normal ALDH2 genotype. These results suggest that the role of oral mucosal and glandular ADHs in salivary acetaldehyde production is minimal and support earlier findings indicating that salivary acetaldehyde production is mainly of microbial origin in subjects with normal ALDH2.     

Low Frequency of the ADH2*2 Allele among Atayal Natives of Taiwan with Alcohol Use Disorders

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 β2 subunit; isozymes containing β₂ sub-units oxidize alcohol faster in vitro than the β₁β₁ isozyme encoded by ADH2*1. Thus, the simplest explanation for these data is that individuals with a β2 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.