Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.

Abstract

BACKGROUND:

It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism.

METHODS:

In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours.

RESULTS:

In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2.

CONCLUSIONS:

Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2.

• Authors: Gaeun Kang, Kyung-Yeol Bae, Sung-Wan Kim, Jin Kim, Hee-Young Shin, Jae-Min Kim, Il-Seon Shin, Jin-Sang Yoon, Jong-Keun Kim
• Journal: Alcoholism, clinical and experimental research (Alcohol Clin Exp Res) Vol. 38 Issue 6 Pg. 1502-9 (Jun 2014) ISSN: 1530-0277 [Electronic] England
• PMID: 24797321 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the Research Society on Alcoholism.

Chemical References

• Ethanol
• ADH1B protein, human
• Alcohol Dehydrogenase
• ALDH2 protein, human
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial
• Acetaldehyde

Topics

• Acetaldehyde (blood)
• Adult
• Alcohol Dehydrogenase (genetics, metabolism)
• Aldehyde Dehydrogenase (genetics, metabolism)
• Aldehyde Dehydrogenase, Mitochondrial
• Alleles
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Ethanol (administration & dosage, blood, pharmacokinetics)
• Genotype
• Humans
• Male
• Young Adult