The induction of hepatic cytochrome P-450 in C57 BL/10 and DBA/2 mice by isosafrole and piperonyl butoxide. A comparative study with other inducing agents.

The formation of cytochrome P-450 metabolite complexes with isosafrole and piperonyl butoxide in vivo in genetically 'responsive' C57 BL/10 mice and 'non-responsive' DBA/2 mice is described. Displacement of the isosafrole metabolite complex can be brought about by incubation with certain type I ligands. The capacity of isosafrole and piperonyl butoxide to induced cytochrome P-450 was evaluated by measurement of biphenyl 2- and 4-hydroxylase, ethoxyresofurin O-deethylase and ethylmorphine N-demethylase and by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis and compared with results obtained for phenobarbitone, 3-methylcholanthrene and pregnenolone-16 alpha-carbonitrile. All four monooxygenase activities were elevated by isosafrole and piperonyl butoxide, as were cytochrome P-450 levels in both strains of mice. There was a large increase in biphenyl 2-hydroxylase in microsomes from isosafrole treated mice of both strains on displacement of the metabolite complex. SDS polyacrylamide gel electrophoresis demonstrated that isosafrole and piperonyl butoxide induce protein bands of mol. wt., 54000 in both the responsive and non-responsive strains. In addition, piperonyl butoxide induces a protein band of mol. wt. 49000 in both strains of mice. The changes in metabolic activities on pretreatment with isosafrole and piperonyl butoxide do not correspond to those seen with any single inducing agent. The differences in the inducing capabilities of isosafrole and 3-methylcholanthrene in the 'non-responsive' DBA/2 strain are discussed with reference to possible mechanisms of induction by benzodioxole (methylenedioxyphenyl) compounds.