CATALYSIS OF DIVERGENT PATHWAYS OF 2-ACETYLAMINOFLUORENE METABOLISM BY MULTIPLE FORMS OF CYTOCHROME-P-450

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (12) , 4456-4459
Abstract
Highly purified forms of rabbit hepatic, microsomal cytochrome P-450 catalyze the N- and ring-hydroxylation of [the carcinogen] 2-acetylaminofluorene (AAF) at different rates. Form 4, the major form of the cytochrome induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in adult rabbit liver, catalyzed the N-hydroxylation of AAF more rapidly than did the other 3 forms. N-Hydroxy-2-acetylaminofluorene accounted for 70% of the metabolites formed by the action of this cytochrome. Form 6, the major form of the cytochrome induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in neonate rabbit liver, and form 3, a constitutive form of the cytochrome, metabolized AAF at 1/2 the rate observed for form 4. Phenols accounted for > 90% of the metabolites produced by these 2 cytochromes. The major phenobarbital-inducible cytochrome P-450, form 2, exhibited practically no catalytic activity (< 1% of the other forms) with AAF as a substrate. Since N- and ring-hydroxylation are thought to represent divergent pathways of carcinogen metabolism (activation vs. detoxification), the differential occurrence of the various cytochrome forms should affect the balance between these 2 reaction pathways. Cytochrome P-450 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin differentially affects the magnitude and direction of in vitro microsomal metabolism of AAF as a function of age.

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