EFFECT OF EXPOSURE OF RABBIT HEPATOCYTES TO SULFUR-CONTAINING ANTHELMINTICS (OXFENDAZOLE AND FENBENDAZOLE) ON CYTOCHROME P4501A1 EXPRESSION

The expression of cytochrome P4501A1 and 1A2 was investigated in rabbi t hepatocytes maintained in primary cultures for 96 hr in the absence or presence of 100 mu M of the benzimidazole anthelmintics oxfendazole or fenbendazole. Total cytochrome P-450, ethoxyresorufin O-deethylase and acetanilide hydroxylase activities were significantly increased i n cell cultures receiving benzimidazoles, These increases were more ma rked after exposure of cultured hepatocytes to oxfendazole (OFZ) than to fenbendazole (FBZ). Western and Northern blot analysis of microsome s and RNA prepared from these cultures revealed increased levels of bo th protein and specific mRNA for P4501A1. The inhibition of these indu ctions in the presence of actinomycin D suggests a transcriptional way of activation of this gene. The ability of OFZ to bind to the Ah rece ptor has been examined. Data obtained from competition experiments wit h dioxin demonstrated that OFZ and other compounds in the benzimidazol e series are not ligand of the Ah receptor. From saturation experiment s and Scatchard plot analysis, rabbit hepatocyte Ah receptor (K-d = 10 .6 nM) seems to belong, as does the human Ah receptor, to a low-affini ty category. Different induction rates obtained with several benzimida zole drugs suggest that the sulfur atom within the molecule is critica l for CYP1A1 induction. The widely used benzimidazole anthelmintics OF Z and FBZ may exert an inducing effect through an original pathway tha t does not require a specific binding step to the Ah receptor. Copyrig ht (C) 1996 Elsevier Science Ltd.