title: Variability in ethanol biodisposition in whites is modulated by polymorphisms in the ADH1B and ADH1C genes.
abstract: Association between genetic variations in alcohol-related enzymes and impaired ethanol biodisposition has not been unambiguously proven, and the effect of many newly described polymorphisms remains to be explored. The aims of this study are to elucidate the influence of genetic factors in alcohol biodisposition and effects. We analyzed alcohol pharmacokinetics and biodisposition after the administration of 0.5 g/kg ethanol; we measured ethanol effects on reaction time and motor time in response to visual and acoustic signals, and we analyzed 13 single nucleotide polymorphism (SNPs) in the genes coding for ADH1B, ADH1C, ALDH2, and CYP2E1 in 250 healthy white individuals. Variability in ethanol pharmacokinetics and biodisposition is related to sex, with women showing a higher area under the curve (AUC) (P = 0.002), maximum concentration (Cmax) (P < 0.001) and metabolic rate (P = 0.001). Four nonsynonymous SNPs are related to decreased alcohol metabolic rates: ADH1B rs6413413 (P = 0.012), ADH1C rs283413 (P < 0.001), rs1693482 (P < 0.001), and rs698 (P < 0.001). Individuals carrying diplotypes combining these mutations display statistically significant decrease in alcohol biodisposition as compared with individuals lacking these mutations. Alcohol effects displayed bimodal distribution independently of sex or pharmacokinetics. Most individuals had significant delays in reaction and motor times at alcohol blood concentrations under 500 mg/L, which are the driving limits for most countries.
  
  
  CONCLUSIONS
  Besides the identification of new genetic factors related to alcohol biodisposition relevant to whites, this study provides unambiguous identification of diplotypes related to variability in alcohol biodisposition.
authors.affiliation: Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez
authors.forename: Segismundo
authors.initials: S
authors.lastname: Galván
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia-Martin
authors.forename: María I
authors.initials: MI
authors.lastname: Ramos
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gutiérrez-Martín
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
mesh_terms: D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000431:Ethanol / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D000431:Ethanol; C489332:ADH1B protein, human; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase