Dependence of specific metabolism of benzo(a)pyrene on the inducer of hydroxylase activity.

Abstract

Summary 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.