title: Molecular investigation of the effects of lindane in rat hepatocytes: microarray and mechanistic studies.
abstract: Although many studies of lindane toxicity have been carried out, we still know little about the underlying molecular mechanisms. We used a microarray specifically designed for studies of the hepatotoxic effects of xenobiotics to evaluate the effects of lindane on specific gene expression in primary cultured rat hepatocytes. These genes were assigned to detoxication processes (CYP3A4, Gsta2, CYP4A1), cell signalling pathways and apoptosis (Eif2b3, Eif2b4, PKC). In this study, we demonstrate that lindane up-regulates PKC by increasing oxidative stress. TEMPO (a well known free radical scavenger) and Ro 31-8220 (an inhibitor of classical PKCs) prevented the inhibition of spontaneous and intrinsic apoptosis pathway (characterised by Bcl-xL induction, Bax down-regulation, caspases inhibition) and the induction of necrosis by lindane in rat hepatocytes. Thus, these findings indicate that several dependent key signalling pathways, including detoxification, apoptosis, PKC activity and redox status maintenance, contribute to lindane-induced toxicity in primary cultured rat hepatocytes. This may account more clearly for the acute and chronic effects of lindane in vivo, with the induction of cell death and tumour promotion, respectively.
authors: Laboratoire de Toxicologie Cellulaire, Moléculaire et Génomique, INRA, UMR 1331 TOXALIM (Research Centre in Food Toxicology), 06903 Sophia Antipolis, France. zucchini@sophia.inra.fr
authors: Nathalie
authors: N
authors: Zucchini-Pascal
authors: Georges
authors: G
authors: de Sousa
authors: Jérôme
authors: J
authors: Pizzol
authors: Roger
authors: R
authors: Rahmani
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015536:Down-Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D007211:Indoles; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D001556:Hexachlorocyclohexane; D011493:Protein Kinase C; D020169:Caspases; C003959:TEMPO; C064758:Ro 31-8220