Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele
Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele
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DOI：
10.1097/fpc.0b013e32832ecf2e
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发表时间：
2009-08-01
影响因子：
2.6
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
目的已有文献表明，在亚洲人中，乙醛脱氢酶-2(ALDH2)基因变异等位基因ALDH2*2的纯合性几乎完全保护酒精中毒，但杂合性只能在不同程度上提供部分保护。对酒精中毒的部分保护作用归因于肝脏残留的ALDH2活性更快地消除乙醛，以及非酒精杂合子在循环中的较低蓄积。然而，克服ALDH2*1/2酒精依赖者的保护的生理基础尚不清楚。方法为了解决这个问题，我们从221名酒精依赖者中招募了27名汉族人酒精依赖男性，年龄和体重指数匹配，控制了正常的肝脏和心血管功能。受试者分为ALDH2*1/*1纯合子(n=13)和ALDH2*1/*2杂合子(n=14)。在中等剂量乙醇(0.5g/kg体重)灌胃130min后，测定血液中乙醇/乙醛/醋酸盐浓度、心脏和颅外/颅内动脉血流动力学参数以及自评主观感觉。结果与ALDH2*1/*1酒精者相比，ALDH2*1/*2酒精者的血液乙醛水平显著升高，心血管反应和主观知觉显著增加。在吸食相同剂量酒精的杂合性酒精者和先前报道的非酒精性杂合子之间发现了相似的血液乙醛水平。然而，ALDH2*1/2酒精者的生理和心理反应强度明显低于非酒精性杂合子。结论这些结果表明，乙醛而不是乙醇或乙酸乙酯是造成杂合性酒精者酒精敏感性反应的主要原因，提示生理耐受和/或先天的低敏感性可能在克服这种阻吓反应中起着关键作用。对于携带不同ALDH2基因的酒精者，提出了乙醛和酒精中毒的潜在药物遗传学分类。药物遗传学与基因组学19：588-599。(C)2009年Wolters Kluwer Health|Lippincott Williams&Wilkins。
Objectives It has been well documented that although homozygosity of the variant aldehyde dehydrogenese-2 (ALDH2) gene allele, ALDH2*2, in Asians almost fully protects against alcoholism, the heterozygosity only affords a partial protection to varying degrees. The partial protection against alcoholism has been ascribed to the faster elimination of acetaldehyde by residual hepatic ALDH2 activity and the lower accumulation in circulation in nonalcoholic heterozygotes. The physiological basis for overcoming the protection in ALDH2*1/*2 alcoholics, however, remains unclear.Methods To address this question, we recruited a total of 27 Han Chinese alcohol-dependent men, matched by age and body mass index, controlled for normal liver and cardiovascular functions, from a population base of 221 alcoholics. The participants were divided into ALDH2*1/*1 homozygotes (n = 13) and ALDH2*1/*2 heterozygotes (n=14). After a moderate dose of ethanol (0.5 g/kg body weight), blood ethanol/acetaldehyde/acetate concentrations, cardiac and extracranial/intracranial arterial hemodynamic parameters, as well as self-rated subjective sensations, were measured for 130 min.Results ALDH2*1/*2 alcoholics exhibited significantly higher blood acetaldehyde levels as well as prominent cardiovascular effects and the subjective perceptions, compared with the ALDH2*1/*1 alcoholics. Comparable profiles of blood acetaldehyde were found between heterozygotic alcoholics and the previously reported nonalcoholic heterozygotes intaking the same dose of ethanol. ALDH2*1/*2 alcoholics revealed, however, significantly lower intensities in both physiologic and psychologic responses than did the nonalcoholic heterozygotes.Conclusion These results indicate that acetaldehyde, rather than ethanol or acetate, is primarily responsible for the observed alcohol sensitivity reactions in heterozygotic alcoholics and suggest that physiological tolerance and/or innate low sensitivity may play a crucial role in overcoming the deterring response. A potential pharmacogenetic classification of acetaldehydism and alcoholism for alcoholics carrying the different ALDH2 genotypes is proposed. Pharmacogenetics and Genomics 19:588-599. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.