title: The protective effects of ascorbic acid, cimetidine, and nifedipine on diethyldithiocarbamate-induced hepatic toxicity in albino rats.
abstract: The aim of the present work was to clarify the involvement of free radicals, cytochrome P450 toxic metabolites, and deregulation of calcium homeostasis in the mechanism of diethyldithiocarbamate (DDC) hepatotoxicity. This was elucidated through the preadministration of ascorbic acid (a free radical scavenger), cimetidine (an inhibitor of cytochrome P450 enzymes), or nifedipine (a calcium-blocking agent) before DDC treatment to male albino rats. DDC was administered either as a single dose [800 mg/kg body weight (b.w.), subcutaneously, s.c.] or daily repeated doses for 30 days (400 mg/kg b.w., s.c.). Oxidative stress indicators [e.g., malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase enzyme (SOD)] showed that single or repeated DDC doses induce an increase in MDA level and a decrease in SOD activity in the liver, whereas it causes depletion in hepatic GSH after a single dose and an elevation in its value after repeated doses. Severe histopathological changes were also observed in the livers of rats treated with single or repeated DDC doses. Ascorbic acid, cimetidine, and nifedipine pretreatments were found to induce highly protective effects against the evinced DDC hepatotoxicity, manifesting that free radical, cytochrome P450, and calcium-dependent processes contribute to DDC liver toxicity. Finally, although multiple mechanisms may be involved in the hepatotoxic changes induced by DDC, calcium disarrangement and free radical formation play a more critical role than cytochrome P450 in metabolic events leading to toxic effects of DDC.
authors.affiliation: Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt.
authors.forename: Khadiga Mohammed
authors.initials: KM
authors.lastname: Gaafa
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Badawy
authors.forename: Alaaeldin A
authors.initials: AA
authors.lastname: Hamza
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002927:Cimetidine / Q000008:administration & dosage / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004050:Ditiocarb / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009543:Nifedipine / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D015415:Biomarkers; D020011:Protective Agents; D008315:Malondialdehyde; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D013482:Superoxide Dismutase; D005978:Glutathione; D009543:Nifedipine; D001205:Ascorbic Acid; D002118:Calcium