![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
GM Raner, AD Vaz and MJ Coon
Department of Biological Chemistry, Medical School, The University of Michigan, Ann Arbor, 48109-0606, USA.
The involvement of a series of microsomal cytochrome P450 (P450) isozymes in all-trans-retinoid metabolism, including the conversion of all-trans-retinal to all-trans-retinoic acid, was previously described. In the current study, we examined the role of seven liver microsomal P450 isozymes in the oxidation of three isomers of retinal. P450 1A1, which was not tested previously, is by far the most active in the conversion of all-trans-, 9-cis-, and 13-cis-retinal to the corresponding acids, as well as in the 4-hydroxylation of all-trans- and 13-cis retinal. In contrast, P450s 2B4 and 2C3 are the most active in the 4-hydroxylation of 9-cis-retinal, with turnover numbers approximately 7 times as great as that of P450 1A1. The inclusion of cytochrome b5 in the reconstituted enzyme system is without effect or inhibitory in most cases but stimulates the 4-hydroxylation of 9-cis- retinal by P450 2B4, giving a turnover of 3.7 nmol of product/min/nmol of this isozyme, the highest for any of the retinoid conversions we have studied. Evidence was obtained for two additional catalytic reactions not previously attributed to P450 oxygenases: the oxidation of all-trans- and 9-cis-retinal to the corresponding 4-oxo derivatives by isoform 1A2, and the oxidative cleavage of the acetyl ester of vitamin A (retinyl acetate) to all-trans-retinal, also by isoform 1A2. The physiological significance of the latter reaction, with a Km for the ester of 32 microM and a Vmax of 18 pmol/min/nmol of P450, remains to be established. We also examined the effect on P450 of citral, a terpenoid alpha, beta-unsaturated aldehyde and a known inhibitor of cytosolic retinoid dehydrogenases. Evidence was obtained that citral is an effective mechanism-based inactivator of isozyme 2B4, with a KI of 44 microM as determined by the oxidation of 1-phenylethanol to acetophenone, and by isozyme 1A2 in the oxidation of all-trans-retinal to the corresponding acid and by isozyme 2B4 in the 4-hydroxylation of all-trans-retinol and retinoic acid. Thus, citral is not suitable for use in attempts to distinguish between retinoid conversions catalyzed by dehydrogenases in the cytoplasm and by P450 cytochromes in the endoplasmic reticulum.
This article has been cited by other articles:
|
|
 |
|
  J. V. Goldstone, H. M. H. Goldstone, A. M. Morrison, A. Tarrant, S. E. Kern, B. R. Woodin, and J. J. Stegeman Cytochrome P450 1 Genes in Early Deuterostomes (Tunicates and Sea Urchins) and Vertebrates (Chicken and Frog): Origin and Diversification of the CYP1 Gene Family Mol. Biol. Evol., December 1, 2007; 24(12): 2619 - 2631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. H. Black and L. C. Quattrochi MOLECULAR CLONING OF THE GUINEA PIG CYP1A2 GENE 5'-FLANKING REGION: IDENTIFICATION OF FUNCTIONAL AROMATIC HYDROCARBON RESPONSE ELEMENT AND CHARACTERIZATION OF CYP1A2 EXPRESSION IN GPC16 CELLS Drug Metab. Dispos., June 1, 2004; 32(6): 595 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Fletcher, A. Hanberg, and H. Hakansson Hepatic Vitamin A Depletion Is a Sensitive Marker of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Exposure in Four Rodent Species Toxicol. Sci., July 1, 2001; 62(1): 166 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Marill, T. Cresteil, M. Lanotte, and G. G. Chabot Identification of Human Cytochrome P450s Involved in the Formation of All-trans-Retinoic Acid Principal Metabolites Mol. Pharmacol., April 13, 2001; 58(6): 1341 - 1348. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. YAMAMOTO, R. ZOLFAGHARI, and A. C. ROSS Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats FASEB J, October 1, 2000; 14(13): 2119 - 2127. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. Stoppie, M. Borgers, P. Borghgraef, L. Dillen, J. Goossens, G. Sanz, H. Szel, C. Van Hove, G. Van Nyen, G. Nobels, et al. R115866 Inhibits All-trans-Retinoic Acid Metabolism and Exerts Retinoidal Effects in Rodents J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 304 - 312. [Abstract] [Full Text]
|
|
|
|
|
|
Q.-Y. Zhang, D. Dunbar, and L. Kaminsky Human Cytochrome P-450 Metabolism of Retinals to Retinoic Acids Drug Metab. Dispos., March 1, 2000; 28(3): 292 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Chen, W. N. Howald, and M. R. Juchau Biosynthesis Of All-trans-Retinoic Acid from All-trans-Retinol: Catalysis of All-trans-Retinol Oxidation by Human P-450 Cytochromes Drug Metab. Dispos., March 1, 2000; 28(3): 315 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Coon, A. D. N. Vaz, D. F. McGinnity, and H.-M. Peng Multiple Activated Oxygen Species in P450 Catalysis. Contributions to Specificity in Drug Metabolism Drug Metab. Dispos., December 1, 1998; 26(12): 1190 - 1193. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. B. Goodman Three independent lines of evidence suggest retinoids as causal to schizophrenia PNAS, June 23, 1998; 95(13): 7240 - 7244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Roos, F. K. Jugert, H. F. Merk, and D. R. Bickers Retinoid Metabolism in the Skin Pharmacol. Rev., June 1, 1998; 50(2): 315 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-N. Marchetti, E. Sampol, H. Bun, H. Scoma, B. Lacarelle, and A. Durand IN VITRO METABOLISM OF THREE MAJOR ISOMERS OF RETINOIC ACID IN RATS. Intersex and Interstrain Comparison Drug Metab. Dispos., May 1, 1997; 25(5): 637 - 646. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. Gilday, M. Gannon, K. Yutzey, D. Bader, and A. B. Rifkind Molecular Cloning and Expression of Two Novel Avian Cytochrome P450 1A Enzymes Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin J. Biol. Chem., December 20, 1996; 271(51): 33054 - 33059. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
