Regio-Related Differential Induction of Hepatic Microsomal Heme Oxygenase and Cytochrome P450 by Substituted Imidazole and Pyridine Compounds in Rats.

Abstract

The effects of variously subsituted pyridine and imidazole compounds and some of their chlorinated derivatives on the induction of hepatic microsomal heme oxygenase (HO) and cytochrome P450 (P450) were investigated in rats. 2-Benzylpyridine was able to induce HO to about 4.4-fold the control levels. 3-Benzylpyridine also increased HO to a lesser extent, but 4-benzylpyridine did not. Benzoylpyridines, phenylpyridines and diphenylmethylpyridines also produced a similar regio-differential induction of HO to benzylpyridines. Of the pyridine compounds examined, 2-phenylpyridine was the most potent inducer of HO. These substituted pyridines also increased the hepatic P450 content by inversely relating to the magnitudes of their abilities to induce HO. These results indicate that the substituted pyridines which have some lipophilic moieties, such as phenyl-, benzyl-, benzoyl- and diphenylmethyl-moieties, bound at the 2-position, but not at the 4-position of the pyridine ring, could induce HO. The substituted imidazoles generally produced a potent induction of P450, and some of them also exhibited HO induction similar to those of the corresponding pyridine compounds. Both 2-(4-chlorobenzyl)-pyridine and 2-(3, 4-dichlorobenzyl) imidazole were more potent inducers of HO than their dechlorinated parent compounds. All of these findings suggest that the substituted pyridine and imidazole compounds produce HO and P450 induction in a regio-related manner with lipophilic moieties, and that the addition of chlorine atom (s) may alter the magnitude of induction of HO in rat liver.