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Dependence of Specific Metabolism of Benzo(a)pyrene on the Inducer of Hydroxylase Activity¹

Cancer Research Institute, University of California, San Francisco, California 94143

Adult male Sprague-Dawley rats were treated with polycyclic hydrocarbons, phenobarbital (PB), or barbital and the induced hydroxylase enzymes in liver and lung were studied in terms of the specific metabolites of benzo (a) pyrene (BP) that were produced in an in vitro incubation system. The metabolite profile produced by phenobarbital- or barbital-induced enzymes differed from that found with the hydrocarbon-induced liver enzymes in that only the production of 4,5-dihydro-4,5-dihydroxy-BP and 3-hydroxy-BP was increased over the control level, while the production of all identified metabolites was increased when the hydrocarbons were used as inducers. An exception was benzo (e) pyrene, which was essentially inactive as an inducer for either liver or lung enzymes. PB and barbital did not increase enzyme activity in the lung, but BP, 3-methylcholanthrene (3-MC), and 1,2-benzanthracene did. When the induced liver enzymes were tested for their ability to activate BP to a bacterial mutagen, it was found that the PB-induced enzymes were much more active than the 3-MC-induced enzymes when low levels (less than 1 mg/ml) of enzyme protein were present in the incubation mixtures. At higher levels of enzyme protein, the 3-MC-induced enzymes were more active. Addition of an epoxide hydrase inhibitor, 1,2-epoxy-3,3,3-trichloropropane, to the test mixtures with PB-induced enzymes greatly increased the mutagenic activity but only slightly increased the activity obtained with the 3-MC-induced enzymes. The conclusions were: (a) PB and polycyclic hydrocarbons induce enzymes in rat liver with different specificities toward BP; (b) the induced enzymes activated BP to a form that was mutagenic for bacteria; (c) inhibition of the epoxide hydrase induced by PB allowed the accumulation of a form of BP that was mutagenic for bacteria, probably the 4,5-epoxide.

¹ Supported by USPHS Grant CA-11939.

Received 2/25/74. Accepted 5/22/74.