Shabtai Yehuda, Fainsod Abraham
Department of Cellular Biochemistry and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Biochem Cell Biol. 2018 Apr;96(2):148-160. doi: 10.1139/bcb-2017-0132. Epub 2017 Oct 5.
Several models have been proposed to explain the neurodevelopmental syndrome induced by exposure of human embryos to alcohol, which is known as fetal alcohol spectrum disorder (FASD). One of the proposed models suggests a competition for the enzymes required for the biosynthesis of retinoic acid. The outcome of such competition is development under conditions of reduced retinoic acid signaling. Retinoic acid is one of the biologically active metabolites of vitamin A (retinol), and regulates numerous embryonic and differentiation processes. The developmental malformations characteristic of FASD resemble those observed in vitamin A deficiency syndrome as well as from inhibition of retinoic acid biosynthesis or signaling in experimental models. There is extensive biochemical and enzymatic overlap between ethanol clearance and retinoic acid biosynthesis. Several lines of evidence suggest that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for the aldehyde dehydrogenase activity available. In adults, this competition also extends to the alcohol dehydrogenase activity. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase, further supporting the competition model. All of the evidence supports the reduction of retinoic acid signaling as the etiological trigger in the induction of FASD.
已经提出了几种模型来解释人类胚胎暴露于酒精所诱发的神经发育综合征，即胎儿酒精谱系障碍（FASD）。其中一个提出的模型表明，存在对维甲酸生物合成所需酶的竞争。这种竞争的结果是在维甲酸信号传导减少的条件下发育。维甲酸是维生素A（视黄醇）的生物活性代谢产物之一，调节许多胚胎发育和分化过程。FASD的发育畸形特征类似于维生素A缺乏综合征中观察到的畸形，以及实验模型中维甲酸生物合成或信号传导受到抑制时所观察到的畸形。乙醇清除和维甲酸生物合成之间存在广泛的生化和酶学重叠。几条证据表明，在胚胎中，乙醛和视黄醛之间会争夺可用的醛脱氢酶活性。在成年人中，这种竞争还扩展到乙醇脱氢酶活性。通过提高视黄醇、视黄醛或视黄醛脱氢酶的水平，可以改善乙醇诱导的发育缺陷。乙醛会抑制视黄醛脱氢酶产生维甲酸，这进一步支持了竞争模型。所有证据都支持维甲酸信号传导减少是诱发FASD的病因触发因素。
