The effects of mebendazole on P4501A activity in rat hepatocytes and HepG2 cells. Comparison with tiabendazole and omeprazole.
Mebendazole is a benzimidazole anthelmintic widely used in veterinary and human therapy. Among benzimidazole derivatives, several drugs with inducing effect on cytochromes P450 can be found. However, the induction capacity of mebendazole on P450s has not been explored yet. In this study, the effects of mebendazole on P4501A activity was tested in primary cultures of rat hepatocytes and in human hepatoma HepG2 cell line. Two known P4501A inducers with benzimidazole structure, tiabendazole and omeprazole, were also included in the experiments with the aim of studying structure-induction relationships. After 24-, 48- and 72-h incubation of rat hepatocytes and HepG2 cells with drugs in various concentrations (0.1-100 microM), enzyme activity associated with P4501A1/2 (EROD, MROD) was measured. In addition, the P4501A1/2 protein levels in both in-vitro systems were determined by Western-blotting. Mebendazole provoked a significant increase in P4501A1/2 protein expression and P4501A activity in both in-vitro systems. Omeprazole caused a significant dose-dependent increase of P4501A activity only in HepG2 cells. Although tiabendazole treatment led to significant increase of P4501A protein level, no effect on P4501A activity was observed in either system. The results demonstrate that mebendazole possesses the ability to significantly induce P4501A. Thus, pharmacological and toxicological consequences of P4501A induction should be taken into account in human therapy. The structure-induction relationships and differences between in-vitro systems used are discussed.
Baliharová
V
V
Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic. 95bav3361@faf.cuni.cz
Skálová
L
L
Maas
R F M
RF
De Vrieze
G
G
Bull
S
S
Fink-Gremmels
J
J
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D000969:Antinematodal Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008463:Mebendazole / Q000494:pharmacology*; D009853:Omeprazole / Q000494:pharmacology*; D051381:Rats; D013827:Thiabendazole / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000897:Anti-Ulcer Agents; D000969:Antinematodal Agents; D004791:Enzyme Inhibitors; D008463:Mebendazole; D003577:Cytochrome P-450 Enzyme System; D009853:Omeprazole; D013827:Thiabendazole