Effect of the adrenal 11-beta-hydroxylase inhibitor metyrapone on human hepatic cytochrome P-450 expression: induction of cytochrome P-450 3A4.
The drug metyrapone in the presence of glucocorticoid has been shown to induce the expression of rat hepatic cytochrome P-450 (CYP) 1A1 mRNA in vivo and in vitro through disruption of endogenous CYP1A1 regulator homeostasis and without either compound's binding to the aryl hydrocarbon receptor. Addition of metyrapone to human liver cancer cell cultures, with or without dexamethasone, did not induce CYP1A1 mRNA, in contrast to the aryl hydrocarbon receptor ligand beta-naphthoflavone. Addition of metyrapone to primary cultures of human hepatocytes also failed to induce detectable levels of CYP1A1 mRNA or CYP1A protein in two separate preparations, whereas the treatment with 2,3,7,8-tetrachlorodibenzo-rho-dioxin or omeprazole induced detectable levels of CYP1A1 mRNA in one preparation and CYP1A protein in both preparations. Addition of metyrapone to human hepatocyte cultures resulted in the induction of CYP3A4 expression. The pregnane X receptor (PXR), which has recently been shown to mediate the transcriptional induction of CYP3A4 expression in response to rifampicin, was activated by metyrapone in CV-1 cells transiently cotransfected with an expression vector encoding the human PXR and a reporter construct containing the everted repeat sequence that confers CYP3A4 induction responsiveness to inducers within its promoter. Metyrapone activated the human PXR at concentrations that also resulted in the induction of CYP3A4 in human cultured hepatocytes. Metyrapone treatment is therefore unlikely to result in the induction of CYP1A1 but may induce the expression of CYP3A4 in humans.
Harvey
J L
JL
Department of Toxicology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, United Kingdom.
Paine
A J
AJ
Maurel
P
P
Wright
M C
MC
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D017931:DNA Primers; D004790:Enzyme Induction / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D008797:Metyrapone / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000302:isolation & purification; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013252:Steroid 11-beta-Hydroxylase; D008797:Metyrapone