Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes

The Journal of Clinical Endocrinology and Metabolism
C LiddleG C Farrell

Abstract

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 6 beta-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 CYP3A...Continue Reading

Citations

Apr 6, 2000·The Biochemical Journal·P Honkakoski, M Negishi
Nov 26, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ravindra N Dhir, Bernard H Shapiro
Jun 2, 2009·Molecular Pharmacology·David J Waxman, Minita G Holloway
Feb 17, 2006·Annals of Clinical Microbiology and Antimicrobials·Jiezhong Chen, Kenneth Raymond
Mar 2, 2010·The Journal of Clinical Endocrinology and Metabolism·Alexander T Faje, Ariel L Barkan
Mar 10, 2004·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Ram P GuptaNorman H Bell
Nov 5, 2013·Journal of Pharmaceutical and Biomedical Analysis·Lies De BockJan Van Bocxlaer
Aug 8, 2007·Cancer Chemotherapy and Pharmacology·Evangelos CholongitasMaria Dasenaki

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