The binding to oxidised cytochromes P-450 and inhibition of mixed-function oxidases by aryl-substituted benzimidazoles and related compounds.

A series of benzimidazole derivatives containing additional fused and non-fused aromatic groupings were effective inhibitors of aryl hydrocarbon hydroxylase (PB/AHH) and aminopyrine N-demethylase (ADPM) activities in hepatic microsomes from phenobarbitone(PB)-induced rats. Two structurally similar nitrogen heterocycles, 6-ethoxy-2-methylbenzoxazole and 6-methoxy-2-methylbenzothiazole, were moderately potent inhibitors of PB/AHH and APDM. Only phenanthro(9,10-d)imidazole (I50 = 2.2 X 10(-5) M) and 2-(2'-chlorophenoxy)methylbenzimidazole (I50 = 5.2 X 10(-5) M) were potent inhibitors of AHH activity in hepatic microsomes from 3-methylcholanthrene (3-MC)-induced rats. Five of the compounds were evaluated for the ability to bind to oxidised cytochromes P-450 in microsomal suspensions from induced rats. All compounds except phenanthro(9,10-d)imidazole elicited a type II spectral change with oxidised cytochrome P-450 in PB-induced microsomes, whereas only two compounds produced the type II change in 3-MC-induced microsomes. Two other compounds produced the type I spectral change in 3-MC-induced microsomal suspensions, and phenanthro-(9,10-d)imidazole elicited a reverse type I spectral change in both types of induced microsomes. These results indicate that the precise structure of the benzimidazole derivative can determine the binding type that is observed in oxidised microsomes. It is possible, therefore, that more than a single mode of inhibition of monooxygenase activity is occurring and that inhibition, as well as binding type, is dependent on structure.