Duester Gregg, Mic Felix A, Molotkov Andrei
Onco Developmental Biology Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chem Biol Interact. 2003 Feb 1;143-144:201-10. doi: 10.1016/s0009-2797(02)00204-1.
The ability of vitamin A (retinol) to control growth and development depends upon tissue-specific metabolism of retinol to retinoic acid (RA). RA then functions as a ligand for retinoid receptor signaling. Mouse genetic studies support a role for cytosolic alcohol dehydrogenases (ADH) in the first step (oxidation of retinol to retinaldehyde) and a role for cytosolic retinaldehyde dehydrogenases (RALDH) in the second step (oxidation of retinaldehyde to RA). Mice lacking ADH3 have reduced survival and a growth defect that can be rescued by dietary retinol supplementation, whereas the effect of a loss of ADH1 or ADH4 is noticed only in mice subjected to vitamin A excess or deficiency, respectively. Also, genetic deficiency of both ADH1 and ADH4 does not have additive effects, verifying separate roles for these enzymes in retinoid metabolism. As for the second step of RA synthesis, a null mutation of RALDH2 is embryonic lethal, eliminating most mesodermal RA synthesis, whereas loss of RALDH1 eliminates RA synthesis only in the embryonic dorsal retina with no obvious effect on development. Analysis of RA-rescued RALDH2 mutants has also revealed that RALDH3 and at least one additional enzyme produce RA tissue-specifically in embryos. Collectively, these genetic findings indicate that metabolism of retinol to retinaldehyde is not tissue-restricted as it is catalyzed by ubiquitously-expressed ADH3 (a low activity form) as well as by tissue-specifically expressed ADH1 and ADH4 (high activity forms). In contrast, further metabolism of retinaldehyde to RA is tissue-restricted as all enzymes identified are tissue-specific. An important concept to emerge is that selective expression of enzymes catalyzing the second step is what limits the tissues that can completely metabolize retinol to RA to initiate retinoid signaling.
维生素A（视黄醇）控制生长和发育的能力取决于视黄醇向视黄酸（RA）的组织特异性代谢。然后，RA作为类视黄醇受体信号传导的配体发挥作用。小鼠遗传学研究支持胞质醇脱氢酶（ADH）在第一步（视黄醇氧化为视黄醛）中的作用，以及胞质视黄醛脱氢酶（RALDH）在第二步（视黄醛氧化为RA）中的作用。缺乏ADH3的小鼠存活率降低且有生长缺陷，通过饮食补充视黄醇可挽救该缺陷，而ADH1或ADH4缺失的影响仅分别在维生素A过量或缺乏的小鼠中才会被注意到。此外，ADH1和ADH4的基因缺陷没有累加效应，证实了这些酶在类视黄醇代谢中的不同作用。至于RA合成的第二步，RALDH2的无效突变是胚胎致死性的，消除了大多数中胚层RA合成，而RALDH1的缺失仅消除胚胎背侧视网膜中的RA合成，对发育没有明显影响。对RA挽救的RALDH2突变体的分析还表明，RALDH3和至少一种其他酶在胚胎中组织特异性地产生RA。总的来说，这些遗传学发现表明，视黄醇向视黄醛的代谢不受组织限制，因为它由普遍表达的ADH3（低活性形式）以及组织特异性表达的ADH1和ADH4（高活性形式）催化。相比之下，视黄醛向RA的进一步代谢受组织限制，因为所有已鉴定的酶都是组织特异性的。一个重要的概念是，催化第二步的酶的选择性表达限制了能够将视黄醇完全代谢为RA以启动类视黄醇信号传导的组织。
