Naghibi Bijan, Ghafghazi Taghi, Hajhashemi Valiollah, Talebi Ardeshir, Taheri Diana
Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Hezar Jarib Ave., Isfahan, Iran.
Toxicology. 2007 Apr 11;232(3):192-9. doi: 10.1016/j.tox.2007.01.005. Epub 2007 Jan 14.
One of the major adverse effects of vancomycin (VAN) is nephrotoxicity, which the mechanism is not fully understood. However, there is some evidence that oxidative injury could be involved in its pathogenesis. In this study, we examined two antioxidants 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) a superoxide dismutase mimetic and 2,3-dihydroxybenzoic acid (DHB) an iron chelator in VAN-induced nephrotoxicity in rats. DHB at doses of 50 and 100 mg/kg and tempol at doses of 7.5, 15 and 30 mg/kg were administered subcutaneously to rats 30 min prior to intraperitoneal injection of 200 mg/kg VAN. Drug administrations were done every 12 h for 7 days. In animals which received only VAN, the activity of urinary gamma-glutamyl-transferase (GGT) decreased and the activity of lactate dehydrogenase (LDH) in urine increased significantly compared to controls. Serum urea and creatinine (Cr) concentrations and the weight of animals' kidneys increased and body weights were decreased significantly in this group compared to controls. DHB at both doses normalized the GGT activity, but only at the higher dose restore the LDH activity. Both doses of DHB ameliorated the rise in serum urea and Cr concentrations and improved the changes in kidney and body weights significantly. Tempol did not show any beneficial effects at all. There were marked pathologic changes in tubules of kidneys of VAN treated animals. The tissue injury was prevented by both doses of DHB and there was almost no sign of tubular injury in 100 mg/kg treated group. Tempol in any doses could not prevent the tissue injury and there were significant differences in tissue injury in all tempol treated rats with controls. It seems that VAN-induced nephrotoxicity is at least partly due to free radical formation. Hydroxyl radicals might play a major role in VAN-induced nephrotoxicity, since an iron chelator (DHB) could reverse the adverse effects. However, production of other radicals such as superoxide is also probable.
万古霉素（VAN）的主要不良反应之一是肾毒性，其机制尚未完全明确。然而，有证据表明氧化损伤可能参与其发病过程。在本研究中，我们检测了两种抗氧化剂，超氧化物歧化酶模拟物4-羟基-2,2,6,6-四甲基哌啶-1-氧基（tempol）和铁螯合剂2,3-二羟基苯甲酸（DHB）对万古霉素诱导的大鼠肾毒性的影响。在腹腔注射200mg/kg万古霉素前30分钟，分别以50mg/kg和100mg/kg的剂量皮下注射DHB，以7.5mg/kg、15mg/kg和30mg/kg的剂量皮下注射tempol给大鼠。每12小时给药一次，持续7天。与对照组相比，仅接受万古霉素的动物尿γ-谷氨酰转移酶（GGT）活性降低，尿乳酸脱氢酶（LDH）活性显著升高。该组动物血清尿素和肌酐（Cr）浓度升高，肾脏重量增加，体重显著下降。两种剂量的DHB均可使GGT活性恢复正常，但仅高剂量可恢复LDH活性。两种剂量的DHB均能显著改善血清尿素和Cr浓度的升高，并改善肾脏和体重的变化。Tempol未显示出任何有益作用。接受万古霉素治疗的动物肾脏肾小管有明显的病理变化。两种剂量的DHB均能预防组织损伤，在100mg/kg治疗组几乎没有肾小管损伤的迹象。任何剂量的Tempol均不能预防组织损伤，所有接受Tempol治疗的大鼠与对照组相比，组织损伤存在显著差异。似乎万古霉素诱导的肾毒性至少部分归因于自由基的形成。羟自由基可能在万古霉素诱导的肾毒性中起主要作用，因为铁螯合剂（DHB）可以逆转其不良反应。然而，其他自由基如超氧阴离子的产生也有可能。
