title: Mechanisms of hepatotoxicity of chloroacetonitrile - an end product of water chlorination.
abstract: Chloroacetonitrile is a disinfectant by-product of chlorination of drinking water and is considered as a direct-acting mutagenic and carcinogenic agent. Time-course and dose-response studies were performed to examine the mechanism of chloroacetonitrile-induced hepatotoxicity. In the time-course study, animals were scarified at 2, 4, 6 and 12 h after a single oral dose of chloroacetonitrile (38 mg/kg, p.o.). In the dose-response study, rats were scarified at 2 h after a single oral dose of chloroacetonitrile (9, 19, 38, and 76 mg/kg). In the time-course study chloroacetonitrile induced a significant decrease of hepatic glutathione, and activities of glutathione-S-transferase, glutathione proxidase and superoxide dismutase accompanied with an increase of hepatic malondialdehyde, plasma cytokines (IL-6 & 10 and TNF-α), serum aminotransferases and total bilirubin after 2 h of administration. Maximal alteration of the estimated parameters was observed at 4 h and returned to normal value at 6 h and/or 12 h after chloroacetonitrile treatment. Moreover, the alterations in oxidant, antioxidant parameters, inflammatory cytokines and the liver function tests were dose dependant. Histopathological findings supported the biochemical results. These data indicate that the mechanism of chloroacetonitrile-induced hepatotoxicity may be mediated through depletion of antioxidants, induction of oxidative stress and inflammatory cytokines.
authors.affiliation: Department of Medical Laboratories, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
authors.forename: Osama Mohamed
authors.initials: OM
authors.lastname: Abo-Salem
authors.forename: Mabrouk Mahmoud
authors.initials: MM
authors.lastname: Ghonaim
authors.forename: Saad Salem
authors.initials: SS
authors.lastname: Al-Zahrani
mesh_terms: D000097:Acetonitriles / Q000633:toxicity*; D000818:Animals; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D000637:Transaminases / Q000097:blood; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D018508:Water Purification
chemical_list: D000097:Acetonitriles; D016207:Cytokines; D018836:Inflammation Mediators; D014874:Water Pollutants, Chemical; D008315:Malondialdehyde; C069277:chloroacetonitrile; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D000637:Transaminases; D005978:Glutathione; D001663:Bilirubin