Metabolism of oxazaphosphorines

The alcohol-flush reaction occurs in Asians who inherit the mutant ALDH2*2 allele that produces an inactive aldehyde dehydrogenase enzyme. In these individuals, high blood acetaldehyde levels are believed to be the cause of the unpleasant symptoms that follow drinking. We measured the alcohol elimination rates and intensity of flushing in Chinese subjects in whom the alcohol dehydrogenase ADH2 and ALDH2 genotypes were determined. We also correlated ADH2, ADH3, and ALDH2 genotypes with drinking behavior in 100 Chinese men. We discovered that ADH2*2 and ADH3*1, alleles that encode the high activity forms of alcohol dehydrogenase, as well as the mutant ALDH2*2 allele were less frequent in alcoholics than in controls. The presence of ALDH2*2 was associated with slower alcohol metabolism and the most intense flushing. In those homozygous for ALDH2*1, the presence of two ADH2*2 alleles correlated with slightly faster alcohol metabolism and more intense flushing, although a great deal of variability in the latter was noted.

Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism

Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol [EtOH]) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.

Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review.

Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde.

The class I hepatic alcohol dehydrogenases (ADHs) are primarily responsible for ethanol metabolism in humans. Genetic polymorphism at the ADH2 locus results in the inheritance of isozymes of strikingly different catalytic properties. The most common ADH2 allele, ADH2*1, encodes the low K(m) isozyme subunit beta 1. The ADH2*3 allele encodes a high-activity isozyme subunit of alcohol dehydrogenase, beta 3, identified in approximately 25% of African-Americans. The Vmax of beta 3 beta 3-ADH is 30 times greater than that of the beta 1 beta 1-ADH. Therefore, we hypothesized that the rate of ethanol metabolism, an important factor in the toxicity of ethanol, in persons with beta 3-containing ADH, either beta 3 beta 3- or beta 1 beta 3-ADH, would be faster than that of persons with only beta 1 beta 1-ADH. We tested this hypothesis with ethanol administered orally to healthy, young African-Americans. Three hundred and twenty-six African-American men and women were genotyped using polymerase chain reaction amplification of their leukocyte DNA followed by hybridization with allele-specific probes. One hundred twelve volunteers, selected by genotype, received an oral dose of ethanol designed to produce a blood ethanol concentration of 80 mg/dl (0.080 g/dl), when the blood alcohol concentration-time curve was extrapolated back to time 0. Ethanol metabolic rates (beta 60s) were determined in the 112 subjects from the slope of the pseudolinear portion of the blood ethanol concentration-time curves. The mean beta 60 of African-Americans having beta 3-containing ADH isozymes had significantly faster ethanol elimination rates than those with only beta 1 beta 1-ADH isozymes. There were no significant differences in body weight, ethanol intake in the week before testing, peak breath ethanol concentration, time to peak, or volume of distribution between the genotype groups. Within each of these groups, men had lower ethanol disappearance rates than women. These results demonstrate in vivo the kinetic differences of ADH2 isozymes that may influence individual risk for the effects of ethanol.

ADH2 gene polymorphisms are determinants of alcohol pharmacokinetics.

Isozymes of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were studied in human organs and tissues using sensitive analytical techniques. Both ADH and ALDH showed an extensive polymorphism among different racial groups. In liver extracts and other tissues of Japanese an isozyme of ALDH (ALDH I) with a low Km for acetaldehyde was found to be deficient. The ALDH isozyme deficiency might account for the marked initial sensitivity to alcohol in Orientals owing to their impaired acetaldehyde oxidizing capacity. Significantly low erythrocyte ALDH activity was noted more frequently in chronic alcoholics than in healthy controls. After subcellular fractionation of livers from alcoholics a preferential damage of mitochondrial ALDH isozyme was observed. The metabolism of acetaldehyde has received considerable attention in the past few years, owing to the toxic effects of this substance. Rapid progress has been made in the understanding of the multiple molecular forms of ADH and ALDH in human tissues. Our recent studies have demonstrated that the isozymes of ALDH may play an important role in the pathogenesis of alcohol-related organ damage and in the biological sensitivity to alcohol in certain ethnic groups. A possible protection of ALDH I deficiency against alcoholism in Japanese has been discussed. More recent reports [Imprain et al, 1982; Jones, 1982] indicate that, in addition to the enzymatically active ALDH II, tissues from Orientals deficient in ALDH I isozyme contain enzymatically inactive, immunologically cross-reactive material homologous with ALDH I. Thus, the absence of ALDH I isozyme is not due to a regulatory mutation, a gene deletion, or a nonsense mutation, but probably results from a structural mutation.(ABSTRACT TRUNCATED AT 250 WORDS)

D P Agarwal

Papers

The role of alcohol dehydrogenase and aldehyde dehydrogenase isozymes in alcohol metabolism, alcohol sensitivity, and alcoholism.