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CELLULAR AND MOLECULAR

Growth Hormone Determines Sexual Dimorphism of Hepatic Cytochrome P450 3A4 Expression in Transgenic Mice

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.C., A.-M.Y., K.W.K., L.G.B., F.J.G); Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York (A.-M.Y.); Department of Biology, Division of Cell and Molecular Biology, Boston University, Boston, Massachusetts (C.-S.C., D.J.W.); Laboratory Animal Science Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland (L.F.); and Section of Experimental Medicine and Toxicology, Division of Medicine, Imperial College London, London, United Kingdom (R.J.E.)

The impact of age and sex on the expression of hepatic cytochrome P450 3A4 (CYP3A4) was recently determined in a transgenic mouse line carrying the human CYP3A4 gene. To further investigate the physiological regulation of human CYP3A genes, a novel transgenic mouse line was generated using a bacterial artificial chromosome clone containing both CYP3A4 and CYP3A7 genes. CYP3A7 expression was observed in transgenic mouse fetal livers, whereas CYP3A4 exhibited developmental expression characterized by sexual dimorphism in postpubertal livers. Hepatic CYP3A4 protein and RNA were expressed in immature transgenic male mice and became undetectable after 6 weeks of age, whereas CYP3A4 was expressed in both immature and adult females. CYP3A4 was markedly elevated by the xenobiotic receptor activator phenobarbital in both male and female livers, demonstrating drug induction of the CYP3A4 transgene in this mouse model. Furthermore, continuous infusion of recombinant growth hormone (GH) in transgenic male mice, overriding the pulsatile male plasma GH profile, increased hepatic CYP3A4 mRNA and protein to normal female levels. Continuous GH treatment also feminized the expression of endogenous murine Cyp2b and Cyp3a44 genes. Thus, human CYP3A4 contains all of the gene regulatory sequences required for it to respond to endogenous hormonal regulators of developmental expression and sexual dimorphism, in particular GH. These findings may help elucidate the role of GH in determining the sex-dependent expression of CYP3A4 in human liver and suggest that GH therapy may alter the pharmacokinetic and pharmacodynamic properties of CYP3A4 substrates, leading to enhanced metabolism and disposition of drugs in men.

Address correspondence to: Dr. Frank J. Gonzalez, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892. E-mail: fjgonz{at}helix.nih.gov

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