Duester G
La Jolla Cancer Research Foundation, California 92037.
EXS. 1994;71:279-90. doi: 10.1007/978-3-0348-7330-7_28.
Alcohol dehydrogenase (ADH) is best known as the enzyme which catalyzes the reversible oxidation/reduction of ethanol/acetaldehyde. However, mammalian ADH has also been shown to function in vitro as a retinol dehydrogenase in the conversion of retinol (vitamin A alcohol) to retinoic acid, a hormone which regulates gene expression at the transcriptional level. It is clear that retinol must be converted to more active retinoid forms in order to fulfill its roles in growth, development, and cellular differentiation. An important unsolved issue in retinoid research is the control of retinoic acid synthesis from retinol during differentiation. Several enzymes which participate in the conversion of retinol to retinoic acid in vitro have been isolated, but more information on their relative importance is needed. Human ADH exists as a family of isozymes encoded by seven genes which are differentially expressed in adult and fetal mammalian tissues, being found preferentially in the epithelial cells which are known to synthesize and respond to retinoic acid. Retinoic acid is also known to play a role in neural tube development in vertebrate embryos. Excessive doses of retinoic acid or ethanol are both teratogenic for neural tube development. A relationship may exist between these two types of teratogenesis due to the role of ADH in both retinol and ethanol metabolism and the ability of ethanol to competitively inhibit retinol oxidation. There is a lack of information on the expression patterns of ADH genes in early embryos, but transgenic mouse studies are presented here which show that the human ADH3 gene can be expressed in several mouse embryonic tissues including the neural tube. Thus, ethanol-induced neural tube defects seen in cases of fetal alcohol syndrome may be due to ethanol inhibition of retinol oxidation catalyzed by an embryonic ADH. This could potentially lower retinoic acid levels in the neural tube to the extent that gene expression is not properly regulated, resulting in morphological defects.
酒精脱氢酶（ADH）最为人所知的是催化乙醇/乙醛可逆氧化/还原反应的酶。然而，哺乳动物ADH在体外也被证明可作为视黄醇脱氢酶发挥作用，将视黄醇（维生素A醇）转化为视黄酸，视黄酸是一种在转录水平调节基因表达的激素。显然，视黄醇必须转化为更具活性的类视黄醇形式，才能在生长、发育和细胞分化中发挥作用。类视黄醇研究中一个重要的未解决问题是在分化过程中视黄醇合成视黄酸的控制。已经分离出几种在体外参与视黄醇转化为视黄酸的酶，但关于它们的相对重要性还需要更多信息。人类ADH以同工酶家族的形式存在，由七个基因编码，这些基因在成年和胎儿哺乳动物组织中差异表达，优先存在于已知合成和响应视黄酸的上皮细胞中。视黄酸在脊椎动物胚胎的神经管发育中也发挥作用。过量的视黄酸或乙醇对神经管发育都有致畸作用。由于ADH在视黄醇和乙醇代谢中的作用以及乙醇竞争性抑制视黄醇氧化的能力，这两种致畸作用之间可能存在关联。目前缺乏关于早期胚胎中ADH基因表达模式的信息，但本文介绍的转基因小鼠研究表明，人类ADH3基因可在包括神经管在内的几种小鼠胚胎组织中表达。因此，胎儿酒精综合征病例中出现的乙醇诱导神经管缺陷可能是由于乙醇抑制了胚胎ADH催化的视黄醇氧化。这可能会使神经管中的视黄酸水平降低到基因表达无法正常调节的程度，从而导致形态缺陷。
