Distinct forms of hepatic androgen 6β-hydroxylase induced in the rat by indole-3-carbinol and pregnenolone carbonitrile

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