Computational modeling of a putative fetal alcohol syndrome mechanism.
Fetal alcohol syndrome (FAS) refers to a pattern of birth defects occurring in a subpopulation of children born to women who consume alcohol during pregnancy. The significant medical, social, and economic impact 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 developing organisms. In 1991, Duester and Pullarkat proposed that competition of ethanol with retinol at the alcohol dehydrogenase (ADH) binding site formed the basis of the FAS mechanism. This competition adversely affects the developing fetus caused by deregulation of retinoic acid (RA) homeostasis essential for proper fetal tissue development. Stated concisely, the FAS hypothesis is: 1. Class I ADH catalyzes the rate-limiting step in oxidation of retinol (ROH) to RA, and ethanol (ETOH) to acetic acid, thus establishing competition for ADH between ROH and ETOH. 2. RA is required as a signal molecule for cell differentiation critical for normal fetal morphogenesis. 3. ADH binds ingested ETOH, thus deregulating RA homeostasis leading to improper RA signal transduction. Preliminary results from molecular modeling studies of ROH-ADH and ETOH-ADH structures, and physiologic pharmacokinetic modeling confirm the hypothesis with remarkable fidelity.
Whitmire
D
D
Department of Biological and Agricultural Engineering, Enzyme Engineering Laboratory, Driftmier Engineering Center, Athens, Georgia, USA.
Bowen
J P
JP
Shim
J Y
JY
Whitmire
P S
PS
D000426:Alcohol Dehydrogenase / Q000502:physiology*; D001667:Binding, Competitive / Q000502:physiology; D003198:Computer Simulation; D000431:Ethanol / Q000493:pharmacokinetics; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D008958:Models, Molecular; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism*
D000431:Ethanol; D014212:Tretinoin; D000426:Alcohol Dehydrogenase