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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2411-2416
Copyright © 1998 by The Endocrine Society

Original Studies

Separate and Interactive Regulation of Cytochrome P450 3A4 by Triiodothyronine, Dexamethasone, and Growth Hormone in Cultured Hepatocytes1

Christopher Liddle2, Bryan J. Goodwin, Jacob George3, Michael Tapner and Geoffrey C. Farrell4

Storr Liver Unit, Departments of Clinical Pharmacology (C.L., B.J.G.) and Medicine (J.G., M.T., G.C.F.), University of Sydney at Westmead Hospital, Westmead 2145, Australia

Address all correspondence and requests for reprints to: Dr. C. Liddle, Department of Clinical Pharmacology, Westmead Hospital, Westmead 2145, Australia. E-mail: chrisl{at}westgate.wh.usyd.edu.au

CYP3A4, the predominant cytochrome P450 expressed in human liver, is responsible for the metabolism of endogenous steroids and many drugs. On the basis of pharmacokinetic studies in patients with hormonal derangements and the effects of replacement therapy, it has been suggested that iodothyronines decrease CYP3A4-mediated drug metabolism, whereas glucocorticoids and GH enhance CYP3A4 activity. The aim of the present study, using well differentiated human hepatocytes in primary culture, was to examine directly whether hormonal factors regulate CYP3A4 gene expression. Addition of T3 to primary hepatocytes resulted in a marked reduction of CYP3A4-catalyzed testosterone 6ß-hydroxylase activity and corresponding levels of CYP3A4 protein and messenger ribonucleic acid compared to those in untreated cells. Conversely, both dexamethasone and GH treatment substantially increased CYP3A4 gene expression. None of the hormones studied consistently altered the expression of other human cytochrome P450 genes. We conclude that iodothyronines, glucocorticoids, and GH act directly on human hepatocytes to regulate the expression of CYP3A4, and these effects appear to be exerted at a pretranslational level. Altered regulation of hepatic CYP3A4 is, therefore, likely to account for previous observations concerning the effects of endocrine diseases and hormonal treatments on human cytochrome P450-mediated drug and steroid metabolism.




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