摘要：We examined the effect of N-phenylalkylimidazoles (chain length of 1, 2, 3, 4 and 5 carbon atoms) on the induction of hepatic and renal microsomal cytochrome P450 (P450) content and hepatic P450 species (CYP1A1, CYP1A2, CYP2C6, CYP2E1 and CYP3A2) in male and female rats. Treatment of rats with N-phenylalkylimidazoles resulted in the high magnitude induction of hepatic P450 ; especially, 1-benzylimidazole and 1-(3-phenylpropyl) imidazole were shown to be potent inducers of P450 in male and female rats, respectively. The extent of hepatic P450 induction after treatment with N-phenylalkylimidazoles having an even number of carbon atoms, such as 1-(2-phenylethyl) imidazole, was less than that produced by the compounds with odd carbon numbers (1 or 3 carbon atoms) in both sexes. Thus, the induced levels of hepatic P450 were decreased with increasing methylene bridge except for 1-(2-phenylethyl) imidazole treatment. However, we did not observe such a chain-length differential induction of renal P450 ; 1-(2-phenylethyl) imidazole and 1-benzylimidazole were effective inducers of renal P450 in male and female rats, respectively. Aniline p-hydroxylase activity in male rat liver microsomes was parallel to the increase of P450 content, although N-demethylase activity was not. Immunoblot analysis revealed that the increase in CYP1A2, CYP3A2 and CYP2E1 after treatment with N-phenylalkylimidazoles was parallel to that in total P450 content, but induced levels of CYP2C6 increased in a chain-length dependent manner in both sexes. In addition, induced levels of CYP1A1 after treatment with N-phenylalkylimidazoles were very faint, irrespective of their marked increase in P450 content. These results clearly indicate that phenylalkyl-substituted imidazole compounds cause chain length-and gender-related differential induction of P450 species and hepatic drug-metabolizing enzymes in rats.
