• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Jul 16, 1997; 16(14): 4163–4173.
PMCID: PMC1170042

Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos.

Abstract

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 (P450RA) that specifically metabolizes RA. In vitro, P450RA converts all-trans RA into 5,8-epoxy all-trans RA. P450RA 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 P450RA in cell culture renders the cells hyposensitive to all-trans RA. These functional tests in vitro and in vivo indicate that P450RA inactivates RA. The P450RA 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 P450RA, however, is not necessarily inducible by excess RA. These results suggest that P450RA regulates the intracellular level of RA and may be involved in setting up the uneven distribution of active RA in mammalian embryos.

Full Text

The Full Text of this article is available as a PDF (1.0M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Barua AB, Gunning DB, Olson JA. Metabolism in vivo of all-trans-[11-3H]retinoic acid after an oral dose in rats. Characterization of retinoyl beta-glucuronide in the blood and other tissues. Biochem J. 1991 Jul 15;277(Pt 2):527–531. [PMC free article] [PubMed]
  • Bhat K, McBurney MW, Hamada H. Functional cloning of mouse chromosomal loci specifically active in embryonal carcinoma stem cells. Mol Cell Biol. 1988 Aug;8(8):3251–3259. [PMC free article] [PubMed]
  • Blomhoff R, Green MH, Berg T, Norum KR. Transport and storage of vitamin A. Science. 1990 Oct 19;250(4979):399–404. [PubMed]
  • Brand N, Petkovich M, Krust A, Chambon P, de Thé H, Marchio A, Tiollais P, Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. [PubMed]
  • Chambon P. The retinoid signaling pathway: molecular and genetic analyses. Semin Cell Biol. 1994 Apr;5(2):115–125. [PubMed]
  • Chen Y, Huang L, Russo AF, Solursh M. Retinoic acid is enriched in Hensen's node and is developmentally regulated in the early chicken embryo. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10056–10059. [PMC free article] [PubMed]
  • Durston AJ, Timmermans JP, Hage WJ, Hendriks HF, de Vries NJ, Heideveld M, Nieuwkoop PD. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature. 1989 Jul 13;340(6229):140–144. [PubMed]
  • Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. [PubMed]
  • Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992 Jan 24;68(2):397–406. [PubMed]
  • Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesch JL, Dollé P, Chambon P. Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell. 1994 Sep 23;78(6):987–1003. [PubMed]
  • Thaller C, Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 1987 Jun 18;327(6123):625–628. [PubMed]
  • Kikuta Y, Kusunose E, Endo K, Yamamoto S, Sogawa K, Fujii-Kuriyama Y, Kusunose M. A novel form of cytochrome P-450 family 4 in human polymorphonuclear leukocytes. cDNA cloning and expression of leukotriene B4 omega-hydroxylase. J Biol Chem. 1993 May 5;268(13):9376–9380. [PubMed]
  • White JA, Guo YD, Baetz K, Beckett-Jones B, Bonasoro J, Hsu KE, Dilworth FJ, Jones G, Petkovich M. Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. J Biol Chem. 1996 Nov 22;271(47):29922–29927. [PubMed]
  • Kizaki M, Ueno H, Yamazoe Y, Shimada M, Takayama N, Muto A, Matsushita H, Nakajima H, Morikawa M, Koeffler HP, et al. Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein. Blood. 1996 Jan 15;87(2):725–733. [PubMed]
  • Yasuda Y, Konishi H, Kihara T, Tanimura T. Discontinuity of primary and secondary neural tube in spina bifida induced by retinoic acid in mice. Teratology. 1990 Mar;41(3):257–274. [PubMed]
  • Kraft JC, Schuh T, Juchau M, Kimelman D. The retinoid X receptor ligand, 9-cis-retinoic acid, is a potential regulator of early Xenopus development. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3067–3071. [PMC free article] [PubMed]
  • Lee YM, Osumi-Yamashita N, Ninomiya Y, Moon CK, Eriksson U, Eto K. Retinoic acid stage-dependently alters the migration pattern and identity of hindbrain neural crest cells. Development. 1995 Mar;121(3):825–837. [PubMed]
  • Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A, et al. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992 Jan 23;355(6358):359–361. [PubMed]
  • Lohnes D, Mark M, Mendelsohn C, Dollé P, Dierich A, Gorry P, Gansmuller A, Chambon P. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development. 1994 Oct;120(10):2723–2748. [PubMed]
  • Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. [PubMed]
  • Martini R, Murray M. Participation of P450 3A enzymes in rat hepatic microsomal retinoic acid 4-hydroxylation. Arch Biochem Biophys. 1993 May 15;303(1):57–66. [PubMed]
  • McCormick AM, Napoli JL, Schnoes HK, DeLuca HF. Isolation and identification of 5, 6-epoxyretinoic acid: a biologically active metabolite of retinoic acid. Biochemistry. 1978 Sep 19;17(19):4085–4090. [PubMed]
  • Mizushima S, Nagata S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990 Sep 11;18(17):5322–5322. [PMC free article] [PubMed]
  • Nebert DW, Gonzalez FJ. P450 genes: structure, evolution, and regulation. Annu Rev Biochem. 1987;56:945–993. [PubMed]
  • Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell. 1990 Feb 9;60(3):461–472. [PubMed]
  • Okazawa H, Okamoto K, Ishino F, Ishino-Kaneko T, Takeda S, Toyoda Y, Muramatsu M, Hamada H. The oct3 gene, a gene for an embryonic transcription factor, is controlled by a retinoic acid repressible enhancer. EMBO J. 1991 Oct;10(10):2997–3005. [PMC free article] [PubMed]
  • Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. [PubMed]
  • Pijnappel WW, Hendriks HF, Folkers GE, van den Brink CE, Dekker EJ, Edelenbosch C, van der Saag PT, Durston AJ. The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature. 1993 Nov 25;366(6453):340–344. [PubMed]
  • Reynolds NJ, Fisher GJ, Griffiths CE, Tavakkol A, Talwar HS, Rowse PE, Hamilton TA, Voorhees JJ. Retinoic acid metabolites exhibit biological activity in human keratinocytes, mouse melanoma cells and hairless mouse skin in vivo. J Pharmacol Exp Ther. 1993 Sep;266(3):1636–1642. [PubMed]
  • Roman LJ, Palmer CN, Clark JE, Muerhoff AS, Griffin KJ, Johnson EF, Masters BS. Expression of rabbit cytochromes P4504A which catalyze the omega-hydroxylation of arachidonic acid, fatty acids, and prostaglandins. Arch Biochem Biophys. 1993 Nov 15;307(1):57–65. [PubMed]
  • Ruberte E, Dolle P, Chambon P, Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development. 1991 Jan;111(1):45–60. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...