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.
A series of 2-n-alkylbenzimidazoles inhibited cytochrome P-450 dependent aryl hydrocarbon hydroxylase (AHH) and aminopyrine N-demethylase (APDM) activities in phenobarbitone (PB) induced rat liver microsomes. 2-Un-decylbenzimidazole was the most potent compound in the series, having I50 values of 1.8 X 10(-5) and 1.5 X 10(-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 = 2.6 X 10(-4) M) than PB-induced (I50 = 8.4 X 10(-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.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats
D001562:Benzimidazoles; D008748:Methylcholanthrene; D011335:Proadifen; D001189:Aryl Hydrocarbon Hydroxylases; D000633:Aminopyrine N-Demethylase; D010634:Phenobarbital