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首页> 外文期刊>Clinical and experimental pharmacology & physiology >Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo
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Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo

机译:评价组氨酸铜对铜转运体1介导的铂积累和奥沙利铂诱导的体内和体外神经毒性的影响

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The purpose of the present study was to determine whether copper histidine could inhibit copper transporter 1 (Ctr1)-mediated transport of oxaliplatin in vitro and thereby limit the accumulation of platinum and neurotoxicity of oxaliplatin in dorsal root ganglion (DRG) tissue in vivo. In HEK293 cells overexpressing rat Ctr1, copper histidine was shown to be transported by Ctr1 and to inhibit their Ctr1-mediated uptake of oxaliplatin. Pilot in vivo dose-finding studies showed that copper histidine at doses up to 2 mg/kg, p.o., daily for 5 days/week could be added to maximum tolerated doses of oxaliplatin (1.85 mg/kg, i.p., twice weekly) for 8 week combination treatment studies in female Wistar rats. After treatment, rats showed significant changes in sensory neuron size profiles in DRG tissue induced by oxaliplatin that were not altered by its coadministration with copper histidine. The expression of copper transporters (Ctr1 and copper-transporting P-type ATPase 1 (Atp7a)) in DRG tissue appeared unchanged following treatment with oxaliplatin given alone or with copper histidine. Platinum and copper tissue levels were higher in DRG than in most other tissues, but were unaltered by the addition of copper histidine to oxaliplatin treatment.
机译:本研究的目的是确定组氨酸铜是否能在体外抑制铜转运蛋白1(Ctr1)介导的奥沙利铂的转运,从而限制铂在体内和背根神经节(DRG)组织中的神经毒性。在过表达大鼠Ctr1的HEK293细胞中,组氨酸铜被Ctr1转运并抑制其Ctr1介导的奥沙利铂摄取。体内剂量试验研究表明,可以将每天最多5天/周口服2毫克/千克的组氨酸铜与奥沙利铂的最大耐受剂量(1.85毫克/千克,腹腔注射,每周两次)相加8雌性Wistar大鼠进行为期一周的联合治疗研究。治疗后,大鼠显示出由奥沙利铂诱导的DRG组织中感觉神经元大小分布的显着变化,但并未与组氨酸铜共同给药而改变。单独使用奥沙利铂或联合使用组氨酸铜处理后,DRG组织中铜转运蛋白(Ctr1和铜转运P型ATPase 1(Atp7a))的表达未发生变化。 DRG中的铂和铜组织水平高于大多数其他组织,但在奥沙利铂治疗中加入组氨酸铜后并没有改变。

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