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首页> 外文期刊>Pharmacogenetics >Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism.
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Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism.

机译：人类酒精脱氢酶基因家族中的等位基因变异的功能：防止酒精中毒的功能窗口的评估。

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Alcohol dehydrogenase (ADH) catalyses the rate-determining reaction in ethanol metabolism. Genetic association studies of diverse ethnic groups have firmly demonstrated that the allelic variant ADH1B*2 significantly protects against alcoholism but that ADH1C*1, which is in linkage with ADH1B*2, produces a negligible protection. The influence of other potential candidate genes/alleles within the human ADH family, ADH1B*3 and ADH2, remains unclear or controversial. To address this question, functionalities of ADH1B3 and ADH2 were assessed at a physiological level of coenzyme and substrate range. Ethanol-oxidizing activities of recombinant ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2 and ADH2 were determined at pH 7.5 in the presence of 0.5 mm NAD with 2-50 mm ethanol. The activity differences between ADH1B2 and ADH1B1 were taken as a threshold for effective protection against alcoholism and those between ADH1C1 and ADH1C2 as a threshold for null protection. Over 2-50 mm ethanol, the activities of ADH1B3 were found 2.9-23-fold lower than those of ADH1B2, largely attributed to the Km effect (ADH1B2, 1.8 mm; ADH1B3, 61 mm). Strikingly, the ADH1B3 activity was only 84% that of ADH1B1 at a low ethanol concentration, 2 mm, but increased 10-fold at 50 mm. Corrected for relative expression levels of the enzyme in liver, the hepatic ADH2 activities were estimated to be 18-97% those of ADH1B1 over 2-50 mm ethanol and were 28-140% of the activity differences between ADH1C1 and ADH1C2. The assessment based on the proposed functional window for the human ADH gene family indicates that ADH1B*3 may show some degree of protection against alcoholism and that the ADH2 functional variants appear to be negligible for this protection.
机译：酒精脱氢酶（ADH）催化乙醇代谢中的速率决定性反应。对各种族裔的遗传关联研究已坚定地证明，等位基因变体ADH1B * 2可以有效防止酒精中毒，但与ADH1B * 2连接的ADH1C * 1产生的保护作用却微不足道。人类ADH家族中其他潜在候选基因/等位基因ADH1B * 3和ADH2的影响仍然不清楚或存在争议。为了解决这个问题，在生理水平的辅酶和底物范围内评估了ADH1B3和ADH2的功能。在0.5 mm NAD和2-50 mm乙醇存在下，在pH 7.5下测定重组ADH1B1，ADH1B2，ADH1B3，ADH1C1，ADH1C2和ADH2的乙醇氧化活性。将ADH1B2和ADH1B1之间的活性差异作为有效预防酒精中毒的阈值，将ADH1C1和ADH1C2之间的活性差异作为无效保护的阈值。发现在2-50 mm的乙醇中，ADH1B3的活性比ADH1B2低2.9-23倍，这主要归因于Km效应（ADH1B2，1.8 mm; ADH1B3，61 mm）。令人惊讶的是，在2 mm的低乙醇浓度下，ADH1B3的活性仅为ADH1B1的84％，但在50 mm时，其活性增加了10倍。校正该酶在肝脏中的相对表达水平，估计肝脏ADH2的活性是ADH1B1在2-50 mm乙醇上的活性的18-97％，是ADH1C1和ADH1C2之间的活性差的28-140％。基于针对人类ADH基因家族提议的功能窗口的评估表明，ADH1B * 3可能显示出对酒精中毒的某种程度的保护，而ADH2功能变体似乎对于这种保护是微不足道的。

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