Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele.
OBJECTIVE
It has been well documented that although homozygosity of the variant aldehyde dehydrogenase-2 (ALDH2) gene allele, ALDH2*2, in Asians almost fully protects against alcoholism, the heterozygosity only affords a partial protection to varying degrees. The full protection against alcoholism has been ascribed to the low-amount of alcohol hypersensitivity accompanied by a prolonged and large accumulation of acetaldehyde in blood (Peng et al. Pharmacogenetics 1999; 9:463-476). The physiological basis for the partial protection, however, remains unclear.


METHODS
To address this question, we recruited a total of 32 adult Han Chinese men, matched by age, body-mass index, and nutritional state from a population base of 404 men. The subjects were divided into 3 combinatorial genotypic groups of alcohol dehydrogenase (ADH) and ALDH, that is, ALDH2*1/*1-ADH1B*1/*1-ADH1C*1/*1 (n=8), ALDH2*1/*1-ADH1B*2/*2-ADH1C*1/*1 (n=8), and ALDH2*1/*2-ADH1B*2/*2-ADH1C*1/*1 (n=16). Following 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
Heterozygotic ALDH2*1/*2 subjects were found to be strikingly responsive to the moderate amount of alcohol, as evidenced by the prominent cardiovascular effects as well as subjective perceptions of general discomfort for as long as 2 h following ingestion. The ADH1B polymorphisms did not appear to correlate with the pharmacokinetic and pharmacodynamic effects.


CONCLUSIONS
These results indicate that acetaldehyde, rather than ethanol or acetate, is primarily responsible for the observed alcohol sensitivity reactions and suggest that substantially lower accumulation of blood acetaldehyde in the heterozygotes significantly reduces the aversion reaction to low amounts of alcohol that permits other biological as well as environmental factors to facilitate drinking and the according risk for the disease.
Peng
Giia-Sheun
GS
Department of Neurology, Tri-Service General Hospital dDepartment of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC.
Chen
Yi-Chyan
YC
Tsao
Tien-Ping
TP
Wang
Ming-Fang
MF
Yin
Shih-Jiun
SJ
D000079:Acetaldehyde / Q000097:blood / Q000493:pharmacokinetics; D000085:Acetates / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D000437:Alcoholism / Q000235:genetics* / Q000517:prevention & control*; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D002681:China; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010465:Perception / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000085:Acetates; D000431:Ethanol; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde