Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in asian alcoholics, heterozygous for the variant ALDH2*2 gene allele

Yi Chyan Chen, Giia Sheun Peng, Tien Ping Tsao, Ming Fang Wang, Ru Band Lu, Shih Jiun Yin

研究成果: Article同行評審

54 引文 斯高帕斯(Scopus)

摘要

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 (0.5g/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 130min. 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.

原文English
頁(從 - 到)588-599
頁數12
期刊Pharmacogenetics and Genomics
19
發行號8
DOIs
出版狀態Published - 2009 8月

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 分子生物學
  • 遺傳學
  • 藥理學、毒理學和藥劑學 (全部)
  • 遺傳學(臨床)

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