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. Conclusion: 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. (HEPATOLOGY 2010;51:491-500.) E ffects of alcohol drinking vary among individuals.Part of the interindividual differences in the response to alcohol may be attributed to variability in pharmacokinetics, because a large interindividual variation in alcohol concentration exists, even when subjects receive weight-adjusted doses. 1,2 Because variations in alcohol pharmacokinetics are inheritable, 2,3 it has been hypothesized that genetic variations in alcohol-metabolizing enzymes may underlie interindividual variability in the response to alcohol. More than 90% of ingested ethanol is metabolized in humans. 4 The primary step of alcohol ethanol metabolism in human liver is oxidation to acetaldehyde by two enzyme systems, namely alcohol dehydrogenase (ADH1) and the microsomal ethanol oxidizing system, with a prominent role of cytochrome P450 2E1 (CYP2E1). 5 ADH1 is a dimer, and the monomers are encoded by the genes ADH1A, ADH1B, and ADH1C.

Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals.Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses.Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os. Reaction and motor times were determined before ethanol challenge (basal), and when participants reached peak ethanol concentrations. We analyzed all common missense polymorphisms described in the 19 genes coding for the GABA-A receptor subunits by using TaqMan probes.Results: The GABRA6 rs4454083 T/C polymorphisms were related to motor times, with individuals carrying the C/C genotype having faster motor times, both, at basal and at peak ethanol concentrations. The GABRA4 rs2229940 T/T genotype was associated to faster reaction times and with lower ethanol effects, determined as the difference between basal reaction time and reaction time at peak concentrations. All these associations remained significant after correction for multiple comparisons. No significant associations were observed for the common missense SNPs GABRB3 rs12910925, GABRG2 rs211035, GABRE rs1139916, GABRP rs1063310, GABRQ rs3810651, GABRR1 rs12200969 or rs1186902, GABRR2 rs282129, and GABRR3 rs832032.Conclusions: This study provides novel information supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo.