Ethanol inhibition of retinoic acid synthesis as a potential mechanism for fetal alcohol syndrome.
Retinoic acid (RA) is known to act as a signaling molecule during embryonic development, but little is known about the regulation of RA synthesis from retinol. The rate-limiting step in RA synthesis is the oxidation of retinol, a reaction that can be catalyzed by alcohol dehydrogenase (ADH). Ethanol is also a substrate for ADH, and high levels of ethanol inhibit ADH-catalyzed retinol oxidation. This has prompted us to hypothesize that ethanol-induced defects observed in fetal alcohol syndrome involve ethanol inhibition of ADH-catalyzed RA synthesis. Here, we have examined the effect of ethanol on RA levels in cultured mouse embryos by using a bioassay. Treatment with 100 mM ethanol, but no 10 mM, led to a significant decrease in RA detection in 7.5-day-old embryos. Using whole-mount in situ hybridization, we detected mRNA for class IV ADH, but not ethanol-active cytochrome P450 2E1, in 7.5- and 8.5-day-old embryos, indicating that an ADH-linked pathway exists at these stages for metabolizing retinol and ethanol. Thus, the observed ethanol-induced reduction in RA may be caused by ethanol inhibition of retinol oxidation catalyzed by class IV ADH. In our postulated mechanism for fetal alcohol syndrome, this enzyme may well play a crucial role.
Deltour
L
L
The Burnham Institute, La Jolla, California 92037, USA.
Ang
H L
HL
Duester
G
G
D000014:Abnormalities, Drug-Induced / Q000201:enzymology / Q000209:etiology*; D000426:Alcohol Dehydrogenase / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000302:isolation & purification; D000431:Ethanol / Q000494:pharmacology*; D063647:Fetal Alcohol Spectrum Disorders / Q000201:enzymology / Q000209:etiology*; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000032:analysis; D014018:Tissue Distribution; D014212:Tretinoin / Q000378:metabolism*
D012333:RNA, Messenger; D000431:Ethanol; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating