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 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 6 beta-hydroxylation of androsterone (A) and the induction by IC of CYP3A1/2, the P450 isozyme responsible for the bulk of hepatic 6 beta-hydroxylation of 4-androstenedione (AD). The effect of inhibitors on the formation of 6 beta-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 6 beta-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 6 beta, allylic in AD but not in the fully saturated ring system of A. The increased hepatic conversion of A to its biologically less active 6 beta-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.
Jellinck
P H
PH
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Newcombe
A M
AM
Forkert
P G
PG
Martucci
C P
CP
D000735:Androstenedione / Q000378:metabolism; D000738:Androsterone / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006900:Hydroxylation; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013629:Tamoxifen / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D013629:Tamoxifen; D011285:Pregnenolone Carbonitrile; D000735:Androstenedione; D003577:Cytochrome P-450 Enzyme System; C016517:indole-3-carbinol; D000738:Androsterone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D008797:Metyrapone