Aflatoxin B1 hydroxylation by the pregnenolone-16 alpha-carbonitrile-inducible form of rat liver microsomal cytochrome P-450.
The effects of treating rats with various pregnenolone-16 alpha-carbonitrile (PCN)-type inducers of cytochrome P-450p on the liver microsomal metabolism of aflatoxin B1 (AFB1) were investigated. Treatment of male rats with PCN resulted in a 6-fold increase in the 9-hydroxylation of AFB1 to aflatoxin Q1 (AFQ1). Treatment of female rats with PCN resulted in a 16-fold increase in the formation of AFQ1. The age-dependent decline in constitutive cytochrome P-450p levels in female but not male rats resulted in a sex difference in the formation of AFQ1 in liver microsomes from untreated rats (male:female approximately 3:1). The formation of AFQ1 was stimulated up to 5.4-fold when liver microsomes from triacetyloleandomycin (TAO)-treated rats were treated with potassium ferricyanide, which dissociates the complex between cytochrome P-450p and TAO. Treatment of male rats with the cytochrome P-450p inducer, dexamethasone, increased (approximately 7-fold) the 9-hydroxylation of AFB1 to AFQ1 by liver microsomes, and also enhanced (approximately 2-fold) the microsomal activation of AFB1 to metabolites that were mutagenic to Salmonella typhimurium TA98 and TA100. These results indicate that the 9-hydroxylation of AFB1 to AFQ1 is catalyzed by rat liver microsomal cytochrome P-450p.
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000201:enzymology*; D009152:Mutagenicity Tests; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D051381:Rats; D012737:Sex Factors; D014217:Troleandomycin / Q000494:pharmacology
D000348:Aflatoxins; D011285:Pregnenolone Carbonitrile; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D014217:Troleandomycin