Induction of cytochrome P450 2B1 in rat liver by the aromatase inhibitor aminoglutethimide
Murray, M.; Cantrill, E.; Farrell, G.C.
Journal of Pharmacology and Experimental Therapeutics 265(1): 477-481
1993
ISSN/ISBN: 0022-3565 PMID: 8474030 Document Number: 414376
Aminoglutethimide (AG) is an inhibitor of P450 aromatase and is in clinical use for the treatment of estrogen-dependent breast cancer in postmenopausal women. AG produces adrenal insufficiency by inhibition of the adrenal P450 cholesterol side chain cleavage enzyme, but a number of serious pharmacokinetic interactions have been reported between AG and coadministered drugs. The present study was undertaken in the rat to assess the modulatory capacity of AG toward P450 enzyme activities in vitro and in vivo and to identify the P450 subject to such effects. In vivo administration of AG produced a dose-related increase in activities attributable to the hepatic P450 enzyme 2B1. Thus, AG administration (25 and 50 mg/kg, i.p., on 3 consecutive days) resulted in 85 and 100% increases in testosterone 16-beta-hydroxylation and 3.3- and 7.4-fold increases in 7-pentylresorufin O-depentylation (both mediated by P450 2B1) in rat liver; at a dose of 5 mg/kg, no effect on these activities was noted. In addition, microsomes from rats administered high-dose AG catalyzed increased rates of androst-4-ene-3,17-dione 16-beta-hydroxylation (from 0.72 +- 0.10 nmol/min/mg in control to 3.51 +- 0.47 nmol/ min/mg protein). These findings were confirmed by direct immunoquantification of P450 2B1 in hepatic microsomes, by which it was found that the content of the enzyme in control fractions (2.4 +- 0.7 mu-g/mg microsomal protein) was increased 2.9- and 6.5-fold by the respective doses of AG. In contrast, there was no evidence for increases in two other similarly inducible proteins, P450 3A or P450 2C6. In vitro studies in which aminoglutethimide (concentration range 1-200 mu-M) was added to control microsomal incubations demonstrated that the drug was essentially noninhibitory toward constitutive hepatic testosterone hydroxylases. These findings establish that the aromatase inhibitor aminoglutethimide is a phenobarbital-like inducer of hepatic P450 in the rat. Effects of this agent on drug pharmacokinetics in humans in vivo are probably related to P450 induction and unrelated to inhibitory processes.