Samai Mohamed, Sharpe Martyn A, Gard Paul R, Chatterjee Prabal K
Department of Pharmacology and Therapeutics, University of Brighton, Brighton BN2 4GJ, East Sussex, UK.
Free Radic Biol Med. 2007 Aug 15;43(4):528-34. doi: 10.1016/j.freeradbiomed.2007.05.014. Epub 2007 May 16.
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.
百草枯诱导的肾毒性涉及活性氧（ROS）引起的严重肾细胞损伤，具体是通过增加肾脏中超氧阴离子的浓度。最近，已开发出超氧化物歧化酶（SOD）模拟物（SODm），它们具有安全的SOD活性，但也具有额外的抗氧化酶（如过氧化氢酶）或ROS清除活性。本研究的目的是比较两种此类SODm，即具有过氧化氢酶活性的SODm EUK-134和具有ROS清除特性的SODm tempol，对百草枯诱导的肾NRK-52E细胞肾毒性的影响。用百草枯（1 mM）孵育24小时可显著降低细胞活力并增加坏死率。百草枯还产生大量超氧阴离子和羟基自由基。EUK-134（10 - 300 microM）和tempol（0.3 - 1.0 mM）均能够通过歧化或清除超氧阴离子以及减少羟基自由基的产生来提高细胞活力并显著降低百草枯诱导的细胞死亡。此处呈现的数据表明，具有额外过氧化氢酶和/或ROS清除活性的SODm，如EUK-134和tempol，可显著减少百草枯引起的肾细胞损伤。这些作用在避免与较高浓度SOD相关的促氧化活性的浓度下很明显。因此，此类SODm可能被证明是治疗百草枯肾毒性的有益药物。
