INDUCTION OF CYTOCHROME-P450 2B1 IN RAT-LIVER BY THE AROMATASE INHIBITOR AMINOGLUTETHIMIDE

Aminoglutethimide (AG) is an inhibitor of P450 aromatase an is in clin ical use for the treatment of estrogen-dependent breast cancer in post menopausal women. AG produces adrenal insufficiency by inhibition of t he adrenal P450 cholesterol side chain cleavage enzyme, but a number o f serious pharmacokinetic interactions have been reported between AG a nd coadministered drugs. The present study was undertaken in the rat t o assess the modulatory capacity of AG toward P450 enzyme activities i n vitro and in vivo and to identify the P450 subject to such effects. In vivo administration of AG produced a dose-related increase in activ ities attributable to the hepatic P450 enzyme 2B1. Thus, AG administra tion (25 and 50 mg/kg, i.p., on 3 consecutive days) resulted in 85 and 1 00% increases in testosterone 16beta-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 acti vities was noted. In addition, microsomes from rats administered high- dose AG catalyzed increased rates of androst-4-ene-3,17-dione 16beta-h ydroxylation (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 im-mu noquantification of P450 2B1 in hepatic microsomes, by which it was fo und that the content of the enzyme in control fractions (2.4 +/- 0.7 m ug/mg microsomal protein) was increased 2.9- and 6.5-fold by the respe ctive 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 muM) wa s added to control microsomal incubations demonstrated that the drug w as essentially noninhibitory toward constitutive hepatic testosterone hydroxylases. These findings establish that the aromatase inhibitor am inoglutethimide 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 pr ocesses.