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Effect of Microsomal Cytochrome P-450 Isozyme Induction on the Mutagenic Activation of 2-Aminoanthracene

Department of Biochemistry, Research Institute of Scripps Clinic, La Jolla, California 92037

Two rabbit microsomal cytochrome P-450 isozymes, Forms 4 and 6, which are differentially induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the liver in an age-dependent fashion, catalyze the activation of 2-aminoanthracene to a mutagen in the Ames Salmonella mutagenesis assay. We have shown previously that in the presence of saturating concentrations of 2-aminoanthracene, Form 4 is 15-fold more active than Form 6 in the activation of this mutagen. Similar differences in the activation of 2-aminoanthracene are observed between liver microsomes isolated from TCDD-treated adult rabbits, in which Form 4 predominates, and microsomes from rabbit neonates exposed transplacentally to TCDD prior to birth, in which Form 6 predominates. However, when the extent of mutagenesis is limited by the amount of 2-aminoanthracene and is independent of the rate of activation, the number of revertants produced is similar for microsomes isolated from either newborn or adult TCDD-treated rabbits. Under these conditions, the extent of mutagenesis obtained for a given amount of 2-aminoanthracene will depend on the balance between activation and competing reaction pathways leading to detoxication. Thus, differences in the rate of activation between adult and newborn microsomes are probably offset by similar differences in the rates of competing pathways of metabolism. This is consistent with the finding that the overall rate of 2-aminoanthracene metabolism by the adult microsomes is greater than that of the neonate. In order for the extent of mutagenesis to be independent of rate, the half-life of 2-aminoanthracene was seen to be less than approximately 12 min.

¹ Supported by USPHS Fellowship CA05992. Present address: Department of Biochemistry and Drug Metabolism, Hoffmann-LaRoche Inc., Nutley, N. J. 07110.

² Supported by USPHS Grant HD04445. Present address: Department of Pediatrics, New York City Hospital-Cornell Medical Center, New York, N. Y. 10021.

³ Supported by USPHS Grant CA24146. To whom requests for reprints should be addressed, at Department of Biochemistry, Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, La Jolla, Calif. 92037.

Received 8/25/81. Accepted 2/10/82.