Effect of the adrenal 11-beta-hydroxylase inhibitor metyrapone on human hepatic cytochrome P-450 expression: Induction of cytochrome Pp-450 3A4

The drug metyrapone in the presence of glucocorticoid has been shown to ind uce the expression of rat hepatic cytochrome P-450 (CYP) 1A1 mRNA in vivo a nd in vitro through disruption of endogenous CYP1A1 regulator homeostasis a nd without either compound's binding to the aryl hydrocarbon receptor. Addi tion of metyrapone to human liver cancer cell cultures, with or without dex amethasone, did not induce CYP1A1 mRNA, in contrast to the aryl hydrocarbon receptor ligand beta-naphthoflavone. Addition of metyrapone to primary cul tures of human hepatocytes also failed to induce detectable levels of CYP1A 1 mRNA or CYP1A protein in two separate preparations, whereas the treatment with 2,3,7,8-tetrachlorodibenzo-rho-dioxin or omeprazole induced detectabl e levels of CYP1A1 mRNA in one preparation and CYP1A protein in both prepar ations. Addition of metyrapone to human hepatocyte cultures resulted in the induction of CYP3A4 expression. The pregnane X receptor (PXR), which has r ecently been shown to mediate the transcriptional induction of CYP3A4 expre ssion 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 confer s CYP3A4 induction responsiveness to inducers within its promoter. Metyrapo ne activated the human PXR at concentrations that also resulted in the indu ction of CYP3A4 in human cultured hepatocytes. Metyrapone treatment is ther efore unlikely to result in the induction of CYP1A1 but may induce the expr ession of CYP3A4 in humans.