Insights into Gender Bias: Rat Cytochrome P450 3A9
- 1Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas (S.A., C.Y.K, H.W.S.); and2Graduate Center for Toxicology, Chandler Medical Center, University of Kentucky, Lexington, Kentucky (M.V.)
- Dr. Henry W. Strobel, Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, P.O. Box 20708, Houston, TX 77225. E-mail:henry.w.strobel{at}uth.tmc.edu
Abstract
Some members of the CYP3A subfamily show gender-dependent expression. Using quantitative real-time polymerase chain reaction, we report that female rats have 28-fold higher CYP3A9 mRNA levels than males in liver and 3.8-fold higher in lung. Furthermore, the CYP3A9 expression profile in kidney exhibits a regio-specific distribution, i.e., a 10-fold higher expression in cortex compared with medulla. Also, we observed tissue-specific estrogen regulation of the CYP3A9 message. Estrogen treatment caused a significant up-regulation in liver and a marked down-regulation both in the cortex and medulla of the kidney. Upon ovariectomy, hepatic and brain CYP3A9 expression were reduced significantly, but a modest increase in kidney expression was observed. The effects of ovariectomy on CYP3A9 gene expression were reversed upon exogenous estrogen treatment. CYP3A protein levels and hepatic microsomal activity toward benzphetamine after various treatments showed changes parallel to CYP3A9 mRNA levels. We report for the first time that CYP3A9 levels change dramatically during the course of pregnancy.
Footnotes
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This work was supported by Grant MH58297 from the National Institute of Mental Health (Department of Health and Human Welfare) and by a Shell Toxicology Fellowship awarded to S.A. The data presented here form part of the dissertation of Sayeepriyadarshini Anakk submitted to the faculty of the University of Texas Graduate School of Biomedical Sciences in partial fulfillment of the requirements for the Doctor of Philosophy degree.
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DOI: 10.1124/jpet.102.048090
- Abbreviations:
- P450
- cytochrome P450
- QRTPCR
- quantitative real-time polymerase chain reaction
- ER
- estrogen receptor
- OVEX
- ovariectomy
- E2
- estradiol benzoate
- PROG
- progesterone
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- Received December 19, 2002.
- Accepted January 29, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
