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Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos
Author(s) -
Fujii Hideta,
Sato Takashi,
Kaneko Sinya,
Gotoh Osamu,
FujiiKuriyama Yoshiaki,
Osawa Kanju,
Kato Shigeaki,
Hamada Hiroshi
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.14.4163
Subject(s) - biology , retinoic acid , neural crest , embryo , in vitro , microbiology and biotechnology , retinoid , intracellular , tretinoin , in vivo , biochemistry , gene , genetics
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 all‐ trans RA into 5,8‐epoxy all‐ trans RA. P450 RA metabolizes other biologically active RAs such as 9‐ cis RA and 13‐ cis RA, but fails to metabolize their precursors, retinol and retinal. Overexpression of P450 RA in cell culture renders the cells hyposensitive to all‐ trans RA. These functional tests in vitro and in vivo 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.