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.
Animals Aryl Hydrocarbon Hydroxylases