In vivo and in vitro effects of beta-naphthoflavone on cytochrome P-450-dependent testosterone hydroxylase activities in liver microsomes.
Hepatic microsomes from beta-naphthoflavone-treated adult male rats exhibit a 60-86% loss of testosterone 7 alpha-, 16 alpha-, and 6 beta-hydroxylase activities compared to those of untreated animals. Studies were conducted to determine if the loss of mono-oxygenase activities reflected the presence of beta-naphthoflavone in microsomes from treated animals or, rather, involved a change in the constitutive forms of cytochrome P-450 involved in testosterone hydroxylation. In vitro preincubation of microsomes from untreated animals with NADPH and beta-naphthoflavone resulted in a selective 30-40% loss of 16 alpha- and 6 beta-hydroxylase activities, results which suggest that a metabolite of beta-naphthoflavone may selectively inhibit testosterone hydroxylase activities. Hepatic microsomes from untreated sexually immature and adult rats and from beta-naphthoflavone-treated adult male rats were solubilized and each resolved into three or four cytochrome P-450 fractions by ion-exchange chromatography. The various cytochrome fractions were distinguished by their CO-difference spectra and reconstituted catalytic activity. Cytochrome P-450 fractions from beta-naphthoflavone-treated adult male rats exhibited only 10% of the 16 alpha- and 2 beta-hydroxylase activities of the analogous fractions from untreated adult male microsomes. The catalytic activity of the fractions from beta-naphthoflavone-treated adults was similar to that of cytochrome P-450 from sexually immature male rats. These data indicate that in vivo administration of beta-naphthoflavone results in a selective loss of androgen-dependent cytochrome P-450 testosterone hydroxylase activity.
D000375:Aging; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D019324:beta-Naphthoflavone
D000728:Androgens; D001571:Benzoflavones; D005419:Flavonoids; D013739:Testosterone; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster