The effects of fenbendazole, flubendazole and mebendazole on activities of hepatic cytochromes P450 in pig

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Abstract
Fenbendazole (FBZ), flubendazole (FLBZ) and mebendazole (MBZ) are benzimidazole anthelmintics widely used in veterinary medicine. The effects of these drugs on cytochromes P450 (CYP) were investigated in primary cultures of swine (Sus scrofa f. domestica) hepatocytes. After 48-h incubation of hepatocytes with benzimidazoles (0.1-2.5 microm), ethoxyresorufin O-deethylation (EROD), benzoxyresorufin O-dearylation (BROD), testosterone hydroxylase (6beta-TOH) and testosterone oxidase (17-TO) activities were measured and the CYP1A and 3A protein levels were determined by Western blotting. FBZ produced a significant, concentration-dependent increase of CYP1A activity (EROD) and protein level. No enhancement of CYP1A was observed after exposure to FLBZ and MBZ. All benzimidazoles tested did not cause any induction of CYP3A (BROD, 6beta-TOH, 17-TO activities and protein content). On the other hand, MBZ produced a significant, concentration-dependent decrease of CYP3A (BROD, 6beta-TOH and 17-TO) activities. Pharmacological and toxicological consequences of CYP1A induction and CYP3A inhibition should be taken into account in treatment of pigs with FBZ and MBZ.