Campos Fernanda C, Victorino Vanessa J, Martins-Pinge Marli Cardoso, Cecchini Alessandra L, Panis Carolina, Cecchini Rubens
Laboratory of Physiopathology and Free Radicals, Department of Pathology, State University of Londrina, Londrina, Paraná, Brazil.
Faculty of Medicine, Universidade de São Paulo, São Paulo, Brazil.
Food Chem Toxicol. 2014 Jun;68:78-86. doi: 10.1016/j.fct.2014.03.013. Epub 2014 Mar 19.
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 1h using human-equivalent doses (PTX+CREL/ethanol+NaCl 175mg/m(2) or CREL+ethanol+NaCl) and sacrificed immediately or 24h 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 24h after infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, increased catalase activity, and decreased TRAP levels. On the other hand, after 24h, 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.
紫杉醇（PTX）及其增溶剂聚氧乙烯蓖麻油（CREL）的毒性作用在体外已得到充分证实；然而，这种毒性的体内机制仍不清楚。因此，本研究的目的是分析PTX和CREL输注诱导的体内毒性，并研究氧化应激作为这种毒性潜在机制的参与情况。我们使用等效人体剂量（PTX+CREL/乙醇+氯化钠175mg/m²或CREL+乙醇+氯化钠）对雄性Wistar大鼠进行1小时的PTX和/或CREL处理，并在这些药物输注后立即或24小时处死，进行全身生化评估。在一些组中添加了水溶性维生素E（维生素E，曲洛秦）作为对照。通过测量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、血红蛋白谱、血浆总自由基捕获抗氧化参数（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特征。我们的研究结果表明，CREL输注引发了立即的高血浆脂质过氧化并增加了TRAP，而PTX导致了立即的TRAP消耗和高铁血红蛋白形成。输注后24小时检测到明显的氧化作用，此时CREL处理增加了RBC计数和血浆脂质过氧化，增加了过氧化氢酶活性，并降低了TRAP水平。另一方面，24小时后，输注PTX的大鼠显示过氧化氢酶活性降低和高铁血红蛋白水平降低。这些数据表明在CREL-PTX治疗期间存在持续的氧化应激产生，并突出了CREL是体内对RBC氧化损伤的主要原因。
