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Catalysis of Divergent Pathways of 2-Acetylaminofluorene Metabolism by Multiple Forms of Cytochrome P-450

Department of Biochemistry, Scripps Clinic and Research Foundation, La Jolla, California 92037 [E. F. J., U. M-E.], and Biochemical Pharmacology Section, Laboratory of Chemical Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205 [D. S. L., S. S. T.]

Four highly purified forms of rabbit hepatic, microsomal cytochrome P-450 catalyze the N- and ring-hydroxylation of 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 three 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, both metabolized AAF at one-half the rate observed for Form 4. Phenols accounted for more than 90% of the metabolites produced by these two 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 versus detoxification), the differential occurrence of the various cytochrome forms should affect the balance between these two reaction pathways. In this sense, 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.

¹ Recipient of NIH Grant CA-24146. To whom requests for reprints should be addressed, at the Department of Biochemistry, Scripps Clinic and Research Foundation, 10666 N. Torrey Pines Rd., LaJolla, Calif. 92037.

² Recipient of NIH Grant HD-04445.

Received 1/10/80. Accepted 8/22/80.

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