Ali B H, Al Moundhri M S, Tag Eldin M, Nemmar A, Tanira M O
Department of Pharmacology and Clinical Pharmacy, Sultan Qaboos University, PO Box 35, Al Khod 123, Oman.
Fundam Clin Pharmacol. 2007 Oct;21(5):547-53. doi: 10.1111/j.1472-8206.2007.00495.x.
Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent.
合成抗癌药物顺铂（CP）导致肾毒性的发病机制涉及肾皮质中活性氧和自由基的产生，并且半胱氨酸前药L-2-氧代噻唑烷-4-羧酸（OTC）已被证实具有强大的抗氧化作用。因此，在本研究中，我们旨在测试OTC对大鼠CP肾毒性可能的保护或缓解作用。以150mg/kg/天的口服剂量给予OTC，持续7天。在第7天，其中一些大鼠接受一次腹腔注射6mg/kg剂量的CP（或赋形剂）。处死大鼠，收集血液和尿液样本，并在CP治疗6天后取出肾脏。通过光学显微镜进行组织病理学评估肾毒性，并通过测量血清中肌酐和尿素的浓度、肾皮质中还原型谷胱甘肽（GSH）浓度和超氧化物歧化酶（SOD）活性以及进行尿液分析进行生化评估。CP分别使尿素和肌酐的浓度显著增加（P<0.05）约128%和170%。CP治疗使皮质GSH浓度降低约34%（P<0.05），SOD活性降低约28%（P<0.05）。CP治疗显著增加尿量和N-乙酰-β-D-氨基葡萄糖苷酶（NAG）活性，并显著降低渗透压和蛋白质浓度。OTC显著减轻了所有这些影响。盐水和OTC处理大鼠的切片显示近端小管明显正常。然而，CP处理大鼠的肾脏有中度坏死。当CP与OTC同时给予时，这种坏死似乎减轻。OTC处理未显著改变皮质组织中CP的浓度。结果表明，OTC改善了大鼠肾毒性的组织病理学和生化指标。在进一步的药理和毒理学研究之前，OTC可能有潜力作为一种肾保护剂。
