COMPUTATIONAL MODELING OF A PUTATIVE FETAL ALCOHOL SYNDROME MECHANISM

Fetal alcohol syndrome (FAS) refers to a pattern of birth defects occu rring in a subpopulation of children born to women who consume alcohol during pregnancy. The significant medical, social, and economic impac t of FAS is increasing. Particularly hard-hit are African-American and native-American women and children. Over the past two decades, basic and clinical research produced voluminous data on ethanol effects on d eveloping organisms. In 1991, Duester and Pullarkat proposed that comp etition of ethanol with retinol at the alcohol dehydrogenase (ADH) bin ding site formed the basis of the FAS mechanism. This competition adve rsely affects the developing fetus caused by deregulation of retinoic acid (RA) homeostasis essential for proper fetal tissue development. S tated concisely, the FAS hypothesis is: 1. Class I ADH catalyzes the r ate-limiting step in oxidation of retinol (ROH) to RA, and ethanol (ET OH) to acetic acid, thus establishing competition for ADH between ROH and ETOH. 2. RA is required as a signal molecule for cell differentiat ion critical for normal fetal morphogenisis. 3. ADH binds ingested ETC H, thus deregulating RA homeostasis leading to improper RA signal tran sduction. Preliminary results from molecular modeling studies of ROH-A DH and ETOH-ADH structures, and physiologic pharmacokinetic modeling c onfirm the hypothesis with remarkable fidelity.