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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anthelmintics / pharmacology*
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Aryl Hydrocarbon Hydroxylases*
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Benzimidazoles / pharmacology*
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Blotting, Western
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Cambendazole / pharmacology
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Carbamates*
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Cells, Cultured
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2A6
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Cytochrome P-450 CYP2B1
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Cytochrome P-450 Enzyme System / biosynthesis*
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Dactinomycin / pharmacology
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Enzyme Induction
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Gene Expression / drug effects
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Liver / drug effects
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Liver / enzymology*
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Mixed Function Oxygenases / biosynthesis
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Oxidoreductases / biosynthesis
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Rabbits
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Thiabendazole / analogs & derivatives
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Thiabendazole / pharmacology
Substances
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Anthelmintics
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Benzimidazoles
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Carbamates
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Cambendazole
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Dactinomycin
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Cytochrome P-450 Enzyme System
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5-hydroxythiabendazole
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Mixed Function Oxygenases
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Oxidoreductases
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2A6
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Cytochrome P-450 CYP2B1
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carbendazim
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Thiabendazole