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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

Chen, Yi-Chyana; Peng, Giia-Sheunb; Tsao, Tien-Pingc; Wang, Ming-Fangd; Lu, Ru-Bande; Yin, Shih-Jiund

Pharmacogenetics and Genomics: August 2009 - Volume 19 - Issue 8 - p 588-599
doi: 10.1097/FPC.0b013e32832ecf2e
ORIGINAL ARTICLES
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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.

Departments of aPsychiatry

bNeurology

cInternal Medicine, Tri-Service General Hospital

dDepartment of Biochemistry, National Defense Medical Center, Taipei

eDepartment of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Correspondence to Professor Shih-Jiun Yin, Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11453, Taiwan

Tel: +886 2 8792 3100 x18800; fax: +886 2 8792 4818;

e-mail:yinsj@ndmc.idv.tw

Received 13 February 2009 Accepted 30 May 2009

© 2009 Lippincott Williams & Wilkins, Inc.