Biochemical and Biophysical Research Communications 1996-03-27

Structural requirements for the induction of cytochromes P450 by benzimidazole anthelmintic derivatives in cultured rabbit hepatocytes.

X Rey-Grobellet, N Ferre, C Eeckhoutte, G Larrieu, T Pineau, P Galtier

Index: Biochem. Biophys. Res. Commun. 220(3) , 789-94, (1996)

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Abstract

The effect of sulfur-containing benzimidazoles (thiabendazole, 5-hydroxy-thiabendazole, cambendazole) and sulfur-free derivatives (benzimidazole, carbendazim and 5-hydroxycarbendazim) on cytochrome P450 enzymes was investigated in primary cultures of rabbit hepatocytes considered 72 h after plating. Thiabendazole, cambendazole and carbendazim led to a significant dose-dependent increase in both EROD activity and cytochrome P4501A1/2 proteins and mRNA expression. Experiments using actinomycin D strongly suggest that these compounds have a transcriptional control on both CYP1A1 and CYP1A2 genes in primary hepatocytes. Thiabendazole increased both COH activity and P4502A protein levels. We conclude that sulfur is not a prerequisite to the P450 induction potential of benzimidazoles, while 5-hydroxylation leads to inefficient metabolites in terms of inducibility.