Several 1,3-benzodioxoles (BD) and related compounds were studied in relation to their ability to generate metabolite complexes with hepatic cytochrome P-450 following administration in vivo to rats. BD derivatives that formed stable metabolite complexes with cytochrome P-450 were considerably more effective inducers of cytochrome P-450 and aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase (AHH) activity than derivatives that did not form stable complexes. Linear regression analysis showed that AHH activity was well correlated (r = 0.980) with total (i.e. complexed plus uncomplexed) cytochrome P-450 content and was not correlated with levels of uncomplexed cytochrome P-450. Aminopyrine N-demethylase (APDM) activity in hepatic microsomes from rats treated with 1,3-benzodioxoles was moderately correlated in a linear relationship with uncomplexed levels of cytochrome P-450 and not with total cytochrome P-450.

Changes in cytochromes P-450, aminopyrine N-demethylase (APDM), aromatic hydrocarbon (benzo[a]pyrene) hydroxylase (AHH), and type III spectral complex formation were measured in hepatic microsomes of control, phenobarbital (PB)-, and β-naphthoflavone (βNF)-induced rats after a single dose of dihydrosafrole (4-n-propyl-1,2-methylenedioxybenzene, DHS). Time profiles of changes in these microsomal parameters were complex and showed that APDM activities and cytochrome P-450 levels decreased immediately after treatment and were associated with concurrent increases in the intensity of the type III methylenedioxyphenyl (MDP) metabolite/cytochrome P-450 spectral complex. In noninduced rats, both APDM activity and cytochrome P-450 levels returned to control levels between 12 and 24 hr after treatment with DHS and subsequently increased above control levels. In PB- and βNF-induced animals, the inhibitory phases were more prolonged and activity never returned to levels higher than the corresponding controls. AHH activity was increased substantially (two- to three-fold) in all cases after DHS administration. Although displacement of the MDP metabolite/cytochrome P-450 complex with 2-methylbenzimidazole generally led to a marked restoration of cytochrome P-450 levels and partially reversed the inhibition of APDM, it had little or no effect on AHH activities.

Following in vivo administration to rats of equimolar amounts of a series of 4-n-alkoxymethylenedioxybenzene (AMDB) derivatives, hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activities, total cytochrome P-450 levels, and AMDB metabolite-cytochrome P-450 spectral complex (455 nm) formation were well correlated in parabolic relationships with pi, the hydrophobic constant of the n-alkoxy substituent. Each of these parameters increased progressively over control values with increasing carbon chain length of the alkoxy substituent, passed through an optimal value in compounds containing five or six carbon atoms, and subsequently decreased with the higher homologues. AHH activity was highly correlated in linear relationships with total (complexed plus uncomplexed) cytochrome P-450 content and intensity of the 455-nm spectral complex. Aminopyrine N-demethylase activities in microsomes from AMDB-treated rats were not well correlated with cytochrome P-450 levels or spectral complex formation. AMDB metabolite-ferricytochrome P-450 complexes varied considerably in their relative ease of displacement following treatment with 2-n-heptylbenzimidazole, those derived from the n-butoxy to n-hexoxy derivatives being particularly stable toward the displacer. The results are discussed in relation to the possible mechanisms involved in the interactions of methylenedioxyphenyl compounds with cytochrome P-450 and drug oxidation.