HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 5, 3434-3438, January 30, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/5/3434    most recent M305832200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andreola, F. Articles by De Luca, L. M. Search for Related Content PubMed PubMed Citation Articles by Andreola, F. Articles by De Luca, L. M. Social Bookmarking                      What's this?

Mouse Liver CYP2C39 Is a Novel Retinoic Acid 4-Hydroxylase

ITS DOWN-REGULATION OFFERS A MOLECULAR BASIS FOR LIVER RETINOID ACCUMULATION AND FIBROSIS IN ARYL HYDROCARBON RECEPTOR-NULL MICE^*

Fausto Andreola, Graham P. Hayhurst, Gang Luo¶, Stephen S. Ferguson¶, Frank J. Gonzalez, Joyce A. Goldstein, and Luigi M. De Luca||

From the Laboratory of Cellular Carcinogenesis and Tumor Promotion, Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892 and ^¶Laboratory of Pharmacology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Livers of aryl hydrocarbon receptor (AHR)-null mice have high levels of retinoic acid (RA), retinol, and retinyl palmitate. Hepatic accumulation of RA in these mice may be responsible in part for the hepatic phenotype characterized by small liver size and fibrosis. The increased levels of hepatic RA may be due to decreased metabolism of RA to 4-hydroxyretinoic acid. To identify the P450 isoform(s) involved in RA metabolism, liver microsomes from AHR-null and wild-type mice were subjected to Western blotting and probed with antibodies to rat P450s that cross-react with murine forms. Signal intensity in Western blots probed with anti-rat CYP2C6 antibodies correlated with levels of RA 4-hydroxylation. Furthermore, this anti-rat CYP2C6 antibody inhibited RA 4-hydroxylase activity of wild-type mouse liver microsomes to the levels of AHR-null mouse liver. When used to screen a mouse liver cDNA expression library, this antibody exclusively recognized the murine P450 CYP2C39. Catalytic assays of five recombinant mouse CYP2Cs expressed in Escherichia coli revealed that only CYP2C39 was competent for RA 4-hydroxylation (K_m = 812.3 nM and V_max 47.85 (fmol/min/pmol P450)). Real time reverse transcriptase-PCR used to assess the Cyp2C39 mRNA expression showed decreased levels (30%) of this transcript in AHR-null compared with wild-type liver, consistent with decreased protein levels observed by Western blot analysis using an antibody to a CYP2C39-specific peptide. These data show that CYP2C39 catalyzes RA catabolism and thus possibly controls RA levels in mouse liver. Down-regulation of Cyp2C39 is hypothesized to be responsible for the liver phenotype in the AHR-null mouse.

Received for publication, June 3, 2003 , and in revised form, October 27, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: NCI, Bldg. 37, Rm. 4054C, 37 Convent Dr., Bethesda, MD 20892-4255. Tel.: 301-496-2698; Fax: 301-496-8709; E-mail: luigi_de_luca{at}nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Zhang, P. Hu, C. R. Krois, M. A. Kane, and J. L. Napoli Altered vitamin A homeostasis and increased size and adiposity in the rdh1-null mouse FASEB J, September 1, 2007; 21(11): 2886 - 2896. [Abstract] [Full Text] [PDF]

				C. Arrecubieta, M.-H. Lee, A. Macey, T. J. Foster, and F. D. Lowy SdrF, a Staphylococcus epidermidis Surface Protein, Binds Type I Collagen J. Biol. Chem., June 29, 2007; 282(26): 18767 - 18776. [Abstract] [Full Text] [PDF]

				L. Du, M. M. Neis, P. A. Ladd, and D. S. Keeney Differentiation-Specific Factors Modulate Epidermal CYP1-4 Gene Expression in Human Skin in Response to Retinoic Acid and Classic Aryl Hydrocarbon Receptor Ligands J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1162 - 1171. [Abstract] [Full Text] [PDF]

				L. Quadro, L. Hamberger, M. E. Gottesman, V. Colantuoni, R. Ramakrishnan, and W. S. Blaner Transplacental delivery of retinoid: the role of retinol-binding protein and lipoprotein retinyl ester Am J Physiol Endocrinol Metab, June 1, 2004; 286(5): E844 - E851. [Abstract] [Full Text] [PDF]