Thomasson H R, Beard J D, Li T K
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Alcohol Clin Exp Res. 1995 Dec;19(6):1494-9. doi: 10.1111/j.1530-0277.1995.tb01013.x.
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, ADH21, encodes the low K(m) isozyme subunit beta 1. The ADH23 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.
I类肝脏乙醇脱氢酶（ADHs）主要负责人体内乙醇的代谢。ADH2基因座的遗传多态性导致具有显著不同催化特性的同工酶的遗传。最常见的ADH2等位基因ADH21编码低K(m)同工酶亚基β1。ADH23等位基因编码一种高活性的乙醇脱氢酶同工酶亚基β3，在大约25%的非裔美国人中被发现。β3β3-ADH的Vmax比β1β1-ADH的Vmax大30倍。因此，我们推测，含有β3的ADH（即β3β3-ADH或β1β3-ADH）的个体中乙醇代谢速率（乙醇毒性的一个重要因素）会比仅含有β1β1-ADH的个体更快。我们通过给健康的年轻非裔美国人口服乙醇来检验这一假设。对326名非裔美国男性和女性进行基因分型，方法是先对其白细胞DNA进行聚合酶链反应扩增，然后与等位基因特异性探针杂交。根据基因型选择112名志愿者，给予口服剂量的乙醇，当将血乙醇浓度-时间曲线外推至时间0时，该剂量旨在使血乙醇浓度达到80 mg/dl（0.080 g/dl）。根据血乙醇浓度-时间曲线假线性部分的斜率，在112名受试者中测定乙醇代谢速率（β60s）。具有含β3的ADH同工酶的非裔美国人的平均β60乙醇消除率明显快于仅具有β1β1-ADH同工酶的非裔美国人。基因型组之间在体重、测试前一周的乙醇摄入量、呼气乙醇浓度峰值、达到峰值的时间或分布容积方面没有显著差异。在这些组中的每一组内，男性的乙醇消失率低于女性。这些结果在体内证明了ADH2同工酶的动力学差异，这些差异可能会影响个体对乙醇作用的易感性。
