DISTINCT FORMS OF HEPATIC ANDROGEN 6-BETA-HYDROXYLASE INDUCED IN THE RAT BY INDOLE-3-CARBINOL AND PREGNENOLONE CARBONITRILE

The ability of indole-3-carbinol (IC), an anticarcinogen present in cr uciferous vegetables, to induce CYP1A1, CYP1A2, CYP2B1/2, CYP2E1 and C YP3A1/2 in female rat liver was determined by Western analysis using m onoclonal antibodies and compared to effects produced by pregnenolone carbonitrile in animals of both sexes. The ontogeny of induction of th ese cytochrome P450 isozymes in response to oral administration of IC was also investigated. An inverse correlation was observed between the 6 beta-hydroxylation of androsterone (A) and the induction by IC of C YP3A1/2, the P450 isozyme responsible for the bulk of hepatic 6 beta-h ydroxylation of 4-androstenedione (AD). The effect of inhibitors on th e formation of 6 beta-OHA from A or AD was also determined and shown t o differ from their action on the P450 isozymes involved in the format ion of the 6 beta-hydroxylated derivatives of AD or lithocholic acid. The results indicate that the enzyme induced by IC is distinct from th e CYP3A1/2 which catalyzes hydroxylations at position 6 beta, allylic in AD but not in the fully saturated ring system of A. The increased h epatic conversion of A to its biologically less active 6 beta-OHA meta bolite after treatment of female rats with IC could possibly contribut e to the anticarcinogenic action of indole carbinols. It is also propo sed that the action of multiple inducers present in cruciferous and ot her vegetables might produce androgen metabolic profiles very differen t from those produced by individual components isolated from them.