TY - JOUR T1 - <em>ADH2</em> and <em>CYP2E1</em> Genetic Polymorphisms: Risk Factors for Alcohol-Related Birth Defects JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 562 LP - 565 VL - 29 IS - 4 AU - D. Gail McCarver Y1 - 2001/04/01 UR - http://dmd.aspetjournals.org/content/29/4/562.abstract N2 - Considerable variation in offspring outcome occurs following intrauterine ethanol exposure. The mechanism underlying this varying susceptibility may involve genetic differences in ethanol metabolism catalyzed by alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). A recent population study demonstrated a protective role for the ADH-β3 isoform, which is encoded byADH2*3, an allele unique to African Americans. Drinking during pregnancy was associated with lower scores on the Bayley Scales of Infant Developmental Mental Index (MDI), but only in the offspring of mothers without an ADH2*3 allele. Lower MDI scores were associated with the three-way interaction among increasing ethanol intake and maternal and offspring absence of the ADH2*3allele (p &lt; 0.01, analysis of variance, model r2 = 0.09). The protection afforded by this allele is likely secondary to its encoding of the high Km, highVmax ADH-β3 isoenzyme, which would provide more efficient ethanol metabolism at high blood ethanol concentrations. However, the small amount of variance accounted for by theADH2 polymorphism suggests that other genetic and/or environmental factors are also determinants of offspring risk. We recently described a 96-bp insertion polymorphism in theCYP2E1 regulatory region that is associated with enhanced CYP2E1 metabolic ability in the presence of ethanol intake or obesity, conditions associated with CYP2E1 induction (p &lt; 0.01, both). The frequency of the insertion varies across ethnic groups, occurring in about 30% of African Americans and 7% of Caucasians (p &lt; 0.01), and is sufficiently common to impact susceptibility to alcohol-related birth defects. Thus, genetic differences in ADH and CYP2E1 are likely determinants of offspring risk. The American Society for Pharmacology and Experimental Therapeutics ER -