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The role of microsomal drug-metabolizing enzymes in the biliary excretion of 3,4-benzpyrene in the rat.

The carcinogen 3,4-benzpyrene (BP) is rapidly excreted in the bile of rats as its metabolic products. Pretreatment with agents which induce the microsomal drug-metabolizing enzymes (e.g., phenobarbital methylcholanthrene and BP) greatly enhances the rate of biliary excretion of this compound. Both the rates of metabolism and of biiary excretion are enhanced to a similar extent throughout the induction period. Emetime inhibits both the metabolism and the rate of biliary excretion of BP approximately 50%. Male rats both metabolize BP and subsequently excrete its metabolites in the bile at rates approximately 2.5 times the respective rates in females. When BP metabolites are injected, their biliary excretion rate greatly exceeds the rate seen when BP itself is injected. This greater rate of excretion cannot be further increased by treatment with inducing agents. The induction by methylcholanthrene of both the metabolism and the biliary excretion of BP can be partially blocked by ethionine. It has been concluded that conversion to metabolites is the rate-limiting step in the biiary excretion of BP and that the accelerated excretion seen after inducing agents is specifically attributable to enhancement of this metabolic step.