title: 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.affiliation: Division of Clinical Pharmacology , Chonnam National University Hospital, Gwangju, Korea.
authors.forename: Gaeun
authors.initials: G
authors.lastname: Kang
authors.forename: Kyung-Yeol
authors.initials: KY
authors.lastname: Bae
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Il-Seon
authors.initials: IS
authors.lastname: Shin
authors.forename: Jin-Sang
authors.initials: JS
authors.lastname: Yoon
authors.forename: Jong-Keun
authors.initials: JK
authors.lastname: Kim
mesh_terms: D000079:Acetaldehyde / Q000097:blood; D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D008297:Male; D055815:Young Adult
chemical_list: D000431:Ethanol; C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde
keywords: ADH1B
  
  *2; Acetaldehyde; Ethanol; Pharmacokinetics