Structural requirements for the induction of cytochromes P450 by benzimidazole anthelmintic derivatives in cultured rabbit hepatocytes.
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.
Rey-Grobellet
X
X
Laboratoire de Pharmacologie-Toxicologie INRA, Toulouse, France.
Ferre
N
N
Eeckhoutte
C
C
Larrieu
G
G
Pineau
T
T
Galtier
P
P
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002159:Cambendazole / Q000494:pharmacology; D002219:Carbamates; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis; D011817:Rabbits; D013827:Thiabendazole / Q000031:analogs & derivatives / Q000494:pharmacology
D000871:Anthelmintics; D001562:Benzimidazoles; D002219:Carbamates; D002159:Cambendazole; D003609:Dactinomycin; D003577:Cytochrome P-450 Enzyme System; C035151:5-hydroxythiabendazole; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1; C006698:carbendazim; D013827:Thiabendazole