Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos
Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos
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DOI：
10.1093/emboj/16.14.4163
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发表时间：
1997-07-16
期刊：
影响因子：
11.4
通讯作者：
Hamada, H
中科院分区：
文献类型：
--
作者：
Fujii, H;Sato, T;Hamada, H
维甲酸(RA)是一种具有广泛生物活性的生理剂，可调节脊椎动物的发育过程，但对其代谢的分子基础知之甚少，我们发现了一种新的细胞色素P450(RA)，它能在体外将α-反式RA转化为5，8-环氧全反式RA。P450(RA)代谢其他生物活性RAs，如9-cis-RA和W-cis-RA，但不能代谢其前体视黄醇和视黄醇。P450(RA)在细胞培养中的过度表达使细胞对α-反式RA的敏感性降低，这些体外和体内的功能测试表明，P450(RA)可以使RA失活，P450(RA)基因在小鼠发育过程中并不是统一表达的，而是以阶段和区域特异性的方式表达。发育中胚胎的主要表达区域包括颅神经节的后神经板和神经脊细胞，但过量的RA并不一定能诱导P450(RA)的表达。这些结果表明，P450(RA)调节细胞内RA的水平，可能参与了哺乳动物胚胎中活性RA分布不均的原因。
Retinoic acid (RA) is a physiological agent that has a wide range of biological activity and appears to regulate developmental programs of vertebrates, However, little is known about the molecular basis of its metabolism, Here we have identified a novel cytochrome P450 (P450(RA)) that specifically metabolizes RA, In vitro, P450(RA) converts ah-trans RA into 5,8-epoxy all-trans RA. P450(RA) metabolizes other biologically active RAs such as 9-cis RA and W-cis RA, but fails to metabolize their precursors, retinol and retinal. Overexpression of P450(RA) in cell culture renders the cells hyposensitive to ah-trans RA, These functional tests in vitro and in viva indicate that P450(RA) inactivates RA, The P450(RA) gene is not expressed uniformly but in a stage- and region-specific fashion during mouse development. The major expression domains in developing embryos include the posterior neural plate and neural crest cells for cranial ganglia, The expression of P450(RA), however, is not necessarily inducible by excess RA. These results suggest that P450(RA) regulates the intracellular level of RA and may be involved in setting up the uneven distribution of active RA in mammalian embryos.