Bifonazole, but not the structurally-related clotrimazole, induces both peroxisome proliferation and members of the cytochrome P4504A sub-family in rat liver

Male Wistar rats were treated with a low (150 mu mol/kg) and a high (750 mu mol/kg) dose of either clotrimazole or bifonazole. Bifonazole, but not clotrimazole, exhibited the characteristics of a peroxisome proliferator including hepatomegaly (increase in liver:body weight ratio), up to a 4-fold induction of lauric acid omega-hydroxylase activity and an 8-fold induction of palmitoyl-CoA oxidation by rat liver peroxisomes. This induction of enzyme activities was paralleled by increased protein levels as determined by immunochemical analysis for both liver microsomal cytochrome P4504A1 and the peroxisomal trifunctional protein of the beta-oxidation spiral. In contrast, clotrimazole did not increase protein levels of either cytochrome P4504A or the trifunctional protein. Western blot analyses demonstrated that bifonazole also induced P4502B1/2B2, P4503A and P4501A1, but not P4502E1. Clotrimazole induced a similar spectrum of P450s as determined by Western blotting with the exception that this azole was a marginal P4501A1 inducer under the conditions studied. Taken collectively, our data provides evidence that bifonazole is one of the increasingly recognised, non-carboxylate containing xenobiotics that induce both peroxisome proliferation and the cytochrome P4504A sub-family in rat liver.