Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes.
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 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.
Liddle
C
C
Department of Clinical Pharmacology, University of Sydney, Westmead Hospital, Australia. chrisl@westgate.wh.usyd.edu.au
Goodwin
B J
BJ
George
J
J
Tapner
M
M
Farrell
G C
GC
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015203:Reproducibility of Results; D014284:Triiodothyronine / Q000494:pharmacology*
D005938:Glucocorticoids; D012333:RNA, Messenger; D014284:Triiodothyronine; D003907:Dexamethasone; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human