title: Differential oxidative stress responses to D-galactosamine-lipopolysaccharide hepatotoxicity based on real time PCR analysis of selected oxidant/antioxidant and apoptotic gene expressions in rat.
abstract: Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. This study is focused on addressing the mutual relationship and early signals of these mechanisms in the D-galactosamine and lipopolysaccharide (D-GalN/LPS) hepatotoxicity model, with the help of standard liver function and biochemistry tests, histology, and measurement of gene expression by RT-PCR. Intraperitoneal injection of 400 mg/kg D-GalN and 50 μg/kg LPS was able to induce hepatotoxicity in rats, as evidenced by significant increases in liver enzymes (ALT, AST) and raised bilirubin levels in plasma. Heme oxygenase-1 and nitric oxide synthase-2 gene expressions were significantly increased, along with levels of their products, bilirubin and nitrite. The gene expression of glutathione peroxidase 1 remained unchanged, whereas a decrease in superoxide dismutase 1 gene expression was noted. Furthermore, the significant increase in the gene expression of apoptotic genes Bid, Bax and caspase-3 indicate early activation of apoptotic pathways, which was confirmed by histological evaluation. In contrast, the measured caspase-3 activity remained unchanged. Overall, the results have revealed differential oxidative stress and apoptotic responses, which deserves further investigations in this hepatotoxicity model.
authors.affiliation: Institute of Pharmacology, First Faculty of Medicine, Charles University, Prague, Czech Republic. nalekic@hotmail.com
authors.forename: N
authors.initials: N
authors.lastname: Lekić
authors.forename: D
authors.initials: D
authors.lastname: Cerný
authors.forename: A
authors.initials: A
authors.lastname: Hořínek
authors.forename: Z
authors.initials: Z
authors.lastname: Provazník
authors.forename: J
authors.initials: J
authors.lastname: Martínek
authors.forename: H
authors.initials: H
authors.lastname: Farghali
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D001663:Bilirubin / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D005688:Galactosamine / Q000633:toxicity*; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D016877:Oxidants; D005688:Galactosamine; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000410:Alanine Transaminase; D053148:Caspase 3; D001663:Bilirubin; D000094765:Glutathione Peroxidase GPX1; C000722069:Gpx1 protein, rat