Systemic toxicity induced by paclitaxel in vivo is associated with the solvent cremophor EL through oxidative stress-driven mechanisms
Systemic toxicity induced by paclitaxel in vivo is associated with the solvent cremophor EL through oxidative stress-driven mechanisms
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DOI：
10.1016/j.fct.2014.03.013
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发表时间：
2014-06-01
影响因子：
4.3
通讯作者：
Cecchini, Rubens
中科院分区：
文献类型：
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作者：
Campos, Fernanda C.;Victorino, Vanessa J.;Cecchini, Rubens
紫杉醇(PTX)及其增溶剂克霉酚(CREL)的体外毒性作用已被证实，但其体内毒性机制尚不清楚。因此，本研究的目的是分析PTX和CREL的体内毒性，并探讨氧化应激作为这种毒性的潜在机制。用PTX和/或CREL按人体等量剂量(PTX+CREL/乙醇+氯化钠175 mg/m(2)或CREL+乙醇+氯化钠)处理雄性Wistar大鼠1h，并在给药后即刻或24小时处死动物，进行系统生化评价。有些组加入维生素E(VitE，Trolox)作为对照。通过测定红细胞和血浆脂质过氧化、超氧化物歧化酶和过氧化氢酶活性、还原型谷胱甘肽(GSH)水平、红细胞(RBC)计数、血红蛋白(Hb)谱、血浆总自由基捕获性抗氧化剂参数(TRAP)、血浆脂质过氧化、一氧化氮水平和丙二醛水平来确定氧化水平。我们的研究结果表明，CREL输注立即引发高血浆脂质过氧化反应并增加TRAP，而PTX则立即导致TRAP消耗和高铁血红蛋白形成。当CREL治疗后24小时，红细胞计数和血浆脂质过氧化作用增强，过氧化氢酶活性升高，TRAP水平降低时，可检测到明显的氧化作用。另一方面，24小时后，注射PTX的大鼠表现出过氧化氢酶活性和高铁血红蛋白水平的降低。这些数据表明，在CREL-PTX治疗期间，存在持续的氧化应激生成，并强调CREL是体内红细胞氧化损伤的主要责任。(C)2014爱思唯尔有限公司。保留所有权利。
The toxic effects of paclitaxel (PTX) and its solubilizing agent cremophor EL (CREL) have been well established in vitro; however, the in vivo mechanisms underlying this toxicity remain unclear. Thus, the aim of this study was to analyze the in vivo toxicity induced by infusion of PTX and CREL and to investigate the involvement of oxidative stress as a potential mechanism for this toxicity. We treated male Wistar rats with PTX and/or CREL for 1 h using human-equivalent doses (PTX + CREL/ethanol + NaCl 175 mg/m(2) or CREL + ethanol + NaCl) and sacrificed immediately or 24 h after these drug infusions to systemic biochemical evaluations. Hidrosoluble vitamin E (vitE, Trolox) was added as a control in some groups. The oxidative profile was determined by measuring erythrocyte and plasma lipid peroxidation, superoxide dismutase and catalase activities, reduced glutathione (GSH) levels, red blood cell (RBC) counts, hemoglobin profile, plasma total radical-trapping antioxidant parameter (TRAP), plasma lipid peroxidation, nitric oxide levels and malondialdehyde levels. Our findings showed that CREL infusion triggered immediate high plasma lipid peroxidation and augmented TRAP, while PTX caused immediate TRAP consumption and metahemoglobin formation. Pronounced oxidative effects were detected 24 h after infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, increased catalase activity, and decreased TRAP levels. On the other hand, after 24 h, PTX-infused rats showed reduced catalase activity and reduced metahemoglobin levels. These data indicate the existence of a continuous oxidative stress generation during CREL-PTX treatment and highlight CREL as primarily responsible for the in vivo oxidative damage to RBCs. (C) 2014 Elsevier Ltd. All rights reserved.