Deltour L, Ang H L, Duester G
The Burnham Institute, La Jolla, California 92037, USA.
FASEB J. 1996 Jul;10(9):1050-7.
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.
维甲酸（RA）在胚胎发育过程中作为一种信号分子发挥作用，但对于视黄醇合成RA的调控却知之甚少。RA合成的限速步骤是视黄醇的氧化，这一反应可由乙醇脱氢酶（ADH）催化。乙醇也是ADH的底物，高浓度乙醇会抑制ADH催化的视黄醇氧化。这促使我们推测，胎儿酒精综合征中观察到的乙醇诱导缺陷涉及乙醇对ADH催化的RA合成的抑制。在此，我们通过生物测定法研究了乙醇对培养的小鼠胚胎中RA水平的影响。用100 mM乙醇处理，但不是10 mM，导致7.5日龄胚胎中RA检测量显著下降。利用全胚胎原位杂交技术，我们在7.5日龄和8.5日龄胚胎中检测到IV类ADH的mRNA，但未检测到具有乙醇活性的细胞色素P450 2E1的mRNA，这表明在这些阶段存在一条与ADH相关的途径来代谢视黄醇和乙醇。因此，观察到的乙醇诱导的RA减少可能是由于乙醇抑制了IV类ADH催化的视黄醇氧化。在我们推测的胎儿酒精综合征机制中，这种酶很可能起着关键作用。
