Regioselective inhibition of benzo(a)pyrene metabolism by corticosterone in comparison with metyrapone and alpha-naphthoflavone.
Corticosterone was investigated for its ability to inhibit benzo(a)pyrene (BaP) metabolism and was compared to metyrapone and alpha-naphthoflavone. Corticosterone inhibited aryl hydrocarbon hydroxylase (AHH) activity nonlinearly in hepatic microsomes from uninduced, phenobarbital-induced, or 3-methylcholanthrene-induced rats. When compared to the classic inhibitors metyrapone and alpha-naphthoflavone, corticosterone had inhibitory properties similar to each. Metabolism of BaP to dihydrodiols was inhibited at the K-region by corticosterone only in uninduced microsomes. Dihydrodiol formation at the Bay region, which leads to the putative ultimate carcinogen, was not affected by corticosterone in uninduced or phenobarbital-induced microsomes but stimulated in 3-methylcholanthrene-induced microsomes. These findings suggest that corticosterone regioselectively inhibits cytochrome P-450 mediated oxidation of BaP to less mutagenic metabolites while stimulating the formation of highly mutagenic products.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001571:Benzoflavones / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003345:Corticosterone / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005419:Flavonoids / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D001571:Benzoflavones; D005419:Flavonoids; D011725:Pyridines; C013109:metapyrone; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D010424:Pentobarbital; D003345:Corticosterone