title: The fungicide thiabendazole causes apoptosis in rat hepatocytes.
abstract: Many pharmaceutical drugs cause hepatotoxicity in humans leading to severe liver diseases, representing a serious public health issue. This study investigates the ability of the anthelmintic and antifungal drug thiabendazole to cause cell death by apoptosis and metabolic changes in primary cultures of rat hepatocytes. Thiabendazole (200-500 μM) induced apoptosis in hepatocytes after 1 to 24h, causing loss of mitochondrial membrane potential, cytochrome c release from mitochondria, Fas-associated death domain (FADD) translocation from the cytosol to membranes, and activation of caspases-3, -8 and -9. Thus, thiabendazole activated both the mitochondrial and death receptor pathways of apoptosis. Under these conditions, cell death by necrosis was not detected following exposure to thiabendazole (100-500 μM) for 24-48 h, measured by lactate dehydrogenase release and propidium iodide uptake. Furthermore, thiabendazole increased activities of cytochrome P450 (CYP) isoenzymes CYP1A and CYP2B after 24 and 48 h, determined by 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) activities, respectively. An important finding is that thiabendazole can eliminate hepatocytes by apoptosis, which could be a sensitive marker for hepatic damage and cell death. This study improves understanding of the mode of cell death induced by thiabendazole, which is important given that humans and animals are exposed to this compound as a pharmaceutical agent and in an environmental context.
authors.affiliation: Department of Chemistry, Université du Québec à Montréal (University of Quebec at Montreal), Canada; Department of Biological sciences, Université du Québec à Montréal (University of Quebec at Montreal), Canada.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Séïde
authors.affiliation: Department of Chemistry, Université du Québec à Montréal (University of Quebec at Montreal), Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Marion
authors.affiliation: Department of Chemistry, Université du Québec à Montréal (University of Quebec at Montreal), Canada; BioMedical Research Centre, Université du Québec à Montréal (University of Quebec at Montreal), Canada.
authors.forename: Mircea Alexandru
authors.initials: MA
authors.lastname: Mateescu
authors.affiliation: Department of Chemistry, Université du Québec à Montréal (University of Quebec at Montreal), Canada; Department of Biological sciences, Université du Québec à Montréal (University of Quebec at Montreal), Canada; Research Centre for Environmental Toxicology (TOXEN), Université du Québec à Montréal (University of Quebec at Montreal), Canada; BioMedical Research Centre, Université du Québec à Montréal (University of Quebec at Montreal), Canada. Electronic address: averill.diana@uqam.ca.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Averill-Bates
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000633:toxicity*; D000935:Antifungal Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D013827:Thiabendazole / Q000633:toxicity*
chemical_list: D000871:Anthelmintics; D000935:Antifungal Agents; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D007770:L-Lactate Dehydrogenase; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D020169:Caspases; D013827:Thiabendazole
keywords: Apoptosis; Caspase; Hepatotoxicity; Necrosis; Thiabendazole