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首页> 外文期刊>Pharmacogenetics and genomics >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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Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele.

机译：克服乙醛诱导的亚洲酒精中毒的不良反应的药代动力学和药效学基础，所述变异为ALDH2 * 2基因等位基因的杂合子。

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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.
机译：目的：已有充分文献证明，尽管在亚洲人中，醛脱氢酶-2（ALDH2）变异基因ALDH2 * 2的纯合性几乎可以完全防止酒精中毒，但杂合性仅在不同程度上提供了部分保护。防止酒精中毒的部分保护作用归因于残留的肝脏ALDH2活性可以更快地消除乙醛，并且在非酒精性杂合子中循环中的积累较低。但是，尚不清楚在ALDH2 * 1 / * 2酒精中克服保护的生理基础。方法：为解决这个问题，我们从221名酗酒者中招募了27名汉族酒精依赖男性，按年龄和体重指数进行匹配，以控制其正常的肝脏和心血管功能。参与者分为ALDH2 * 1 / * 1纯合子（n = 13）和ALDH2 * 1 / * 2杂合子（n = 14）。适量服用乙醇（0.5 g / kg体重）后，在130分钟内测量血液中乙醇/乙醛/乙酸盐浓度，心脏和颅外/颅内动脉血流动力学参数以及自我评估的主观感觉。结果：与ALDH2 * 1 / * 1酗酒者相比，ALDH2 * 1 / * 2酗酒者表现出明显更高的血液乙醛水平以及显着的心血管效应和主观感觉。在杂合子酒精类药物和先前报道的服用相同剂量乙醇的非酒精类杂合子之间，发现血液乙醛具有可比性。但是，ALDH2 * 1 / * 2酒精中毒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盐，主要负责杂合酒精中所观察到的酒精敏感性反应，并表明生理耐受性和/或固有的低敏感性可能在克服阻遏反应中起关键作用。针对携带不同ALDH2基因型的酒精中毒者，提出了乙醛和酒精中毒的潜在药理遗传分类。

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