Inhibitors of Hepatic Mixed-Function Oxidases. 4. Effects of Benzimidazole and Related Compounds on Aryl Hydrocarbon Hydroxylase Activity from Phenobarbitone and 3-Methylcholanthrene Induced Rats

Article abstract of DOI:10.1021/jm00348a003

A series of 2-n-alkylbenzimidazoles inhibited cytochrome P-450 dependent aryl hydrocarbon hydroxylase (AHH) and aminopyrine N-demethylase (ADPM) activities in phenylbarbitone (PB) induced rat liver microsomes. 2-Undecylbenzimidazole was the most potent compound in the series, having I50 values of 1.8E-5 and 1.5E-5 M against AHH and APDM activities, respectively.Inhibitory activity increased with increasing carbon chain length of the 2-substituent.Regression analysis showed that there was an apparent relationship between inhibitory activity and hydrophobicity (expressed as the octanol/water partition coefficient) for the inhibition of both AHH and APDM activities in PB-induced rat liver, microsomes.In contrast, these compounds showed little or no inhibitory activity toward cytochrome P-448 dependent AHH activity in hepatic microsomes from 3-methylcholanthrene (3-MC) treated rats.Two 5,6-dimethylbenzimidazoles showed slight inhibitory activity and naphtho<2,3:4'5'>imidazole was only threefold less active toward 3-MC-induced (I50 = 2.6E-4 M) than PB-induced (I50 = 8.4E-5) AHH activity.These results suggest that for nitrogen heterocycles there may be a relationship of increasing polycyclic size and increasing inhibitory activity toward AHH activity in 3-MC-induced rat liver microsomes.