title: Comparison of the effects of the superoxide dismutase mimetics EUK-134 and tempol on paraquat-induced nephrotoxicity.
abstract: Paraquat-induced nephrotoxicity involves severe renal cell damage caused by reactive oxygen species (ROS), specifically via increasing concentrations of superoxide anions in the kidney. Recently, superoxide dismutase (SOD) mimetics (SODm) have been developed that display safe SOD activities but which also possess additional antioxidant enzyme (e.g., catalase) or ROS-scavenging activities. The aim of this study was to compare the effects of two such SODm, specifically, EUK-134, a SODm with catalase activity, and tempol, a SODm with ROS-scavenging properties, on paraquat-induced nephrotoxicity of renal NRK-52E cells. Incubation with paraquat (1 mM) for 24 h reduced cell viability and increased necrosis significantly. Paraquat also generated significant quantities of superoxide anions and hydroxyl radicals. Both EUK-134 (10-300 microM) and tempol (0.3-1.0 mM) were able to improve cell viability and reduced paraquat-induced cell death significantly via dismutation or scavenging of superoxide anions and reduced hydroxyl radical generation. The data presented here suggest that SODm such as EUK-134 and tempol, which possess additional catalase and/or ROS-scavenging activities, can significantly reduce renal cell damage caused by paraquat. These effects were evident at concentrations which avoid the pro-oxidant activities associated with higher concentrations of SOD. Such SODm could therefore prove to be beneficial as therapies for paraquat nephrotoxicity.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Brighton, Brighton BN2 4GJ, East Sussex, UK.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Samai
authors.forename: Martyn A
authors.initials: MA
authors.lastname: Sharpe
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gard
authors.forename: Prabal K
authors.initials: PK
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006540:Herbicides / Q000633:toxicity; D017665:Hydroxyl Radical / Q000378:metabolism; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy; D009942:Organometallic Compounds / Q000494:pharmacology*; D010269:Paraquat / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; C433928:EUK-134; D016166:Free Radical Scavengers; D006540:Herbicides; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; D013113:Spin Labels; D013481:Superoxides; D017665:Hydroxyl Radical; D013482:Superoxide Dismutase; D010269:Paraquat; C001803:tempol