Polymorphism of ethanol-metabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences
Polymorphism of ethanol-metabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences
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DOI：
10.1016/j.cbi.2008.10.029
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发表时间：
2009-03-16
影响因子：
5.1
通讯作者：
Yin, Shih-Jiun
中科院分区：
文献类型：
--
作者：
Chen, Yi-Chyan;Peng, Giia-Sheun;Yin, Shih-Jiun
乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）是负责乙醇代谢的主要酶。ADH和ALDH在种族群体中均表现出遗传多态性。功能性变体等位基因ADH 1B *2和ALDH 2 *2一直被复制，以显示对酒精依赖的保护作用。多因素Logistic回归分析表明，ADH 1B *2和ALDH 2 *2可能独立影响酒精中毒的风险。ALDH 2 *2的纯合性几乎可以完全防止酒精中毒，而杂合性仅在不同程度上提供部分保护。血液乙醇和乙醛浓度，心血管血流动力学反应和主观感觉的相关性已在不同的ADH 1B和ALDH 2基因型组合的男性中进行了研究，这些男性在乙醇激发后持续130分钟。药代动力学和药效学结果表明，乙醛，而不是乙醇，是观察到的酒精敏感性反应的主要原因，这表明ALDH 2 *2/*2的完全保护作用可归因于摄入少量酒精后持续升高的血液乙醛引起的强烈的令人不快的生理和心理反应，而ALDH 2 *1/*2的部分保护作用可归因于乙醛的更快消除和循环中更低的积累。ADH 1B多态性不会显着促进血液乙醛的积累。生理耐受性或对乙醛的先天不敏感性可能对携带ALDH 2 *2的酗酒者的酒精依赖的发展至关重要。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for metabolism of ethanol. Both ADH and ALDH exhibit genetic polymorphisms among racial populations. Functional variant alleles ADH1B*2 and ALDH2*2 have been consistently replicated to show protection against developing alcohol dependence. Multiple logistic regression analyses suggest that ADH1B*2 and ALDH2*2 may independently influence the risk for alcoholism. It has been well documented that homozygosity of ALDH2*2 almost fully protects against developing alcoholism and that the heterozygosity only affords a partial protection to varying degrees. Correlations of blood ethanol and acetaldehyde concentrations, cardiovascular hemodynamic responses, and subjective perceptions have been investigated in men with different combinatorial ADH1B and ALDH2 genotypes following challenge with ethanol for a period of 130 min. The pharmacokinetic and pharmacodynamic consequences indicate that acetaldehyde, rather than ethanol, is primarily responsible for the observed alcohol sensitivity reactions, suggesting that the full protection by ALDH2*2/*2 can be ascribed to the intense unpleasant physiological and psychological reactions caused by persistently elevated blood acetaldehyde after ingesting a small amount of alcohol and that the partial protection by ALDH2*1/*2 can be attributed to a faster elimination of acetaldehyde and the lower accumulation in circulation. ADH1B polymorphism does not significantly contribute to buildup of the blood acetaldehyde. Physiological tolerance or innate insensitivity to acetaldehyde may be crucial for development of alcohol dependence in alcoholics carrying ALDH2*2. (C) 2008 Elsevier Ireland Ltd. All rights reserved.