Aflatoxin b₁ hydroxylation by the pregnenolone-16α-carbonitrile-inducible form of rat liver microsomal cytochrome p-450

The effects of treating rats with various pregnenolone-16α-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 ∼ 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 (∼ 7-fold) the 9-hydroxylation of AFB₁ to AFQ₁ by liver microsomes, and also enhanced (∼ 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.