Inhibition of γ-glutamyl transpeptidase or cysteine S-conjugate β-lyase activity blocks the nephrotoxicity of cisplatin in mice
Inhibition of γ-glutamyl transpeptidase or cysteine S-conjugate β-lyase activity blocks the nephrotoxicity of cisplatin in mice
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DOI：
10.1124/jpet.300.1.142
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发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Hanigan, MH
中科院分区：
文献类型：
--
作者：
Townsend, DM;Hanigan, MH
顺铂有肾毒性。这种器官特异性毒性的机制尚不清楚。我们假设顺铂是通过γ -谷氨酰转肽酶（GGT）和半胱氨酸s -缀合β -裂解酶依赖途径代谢的，该途径已被证明可以激活几种卤代烃为肾毒素。为了验证这一假设，我们在C57BL/6小鼠中抑制GGT和半胱氨酸s -共轭β -裂解酶，并分析了抑制剂对顺铂肾毒性的影响。用acivicin预处理小鼠可抑制GGT。氨基乙酸（AOAA）对半胱氨酸s缀合β -裂解酶有抑制作用。雄性C57BL/6小鼠给予15 mg/kg顺铂（i.p）治疗，第5天处死。单用顺铂治疗的小鼠有一半在献祭前死亡。顺铂治疗5天后处死的小鼠血尿素氮（BUN）水平显著升高。组织学分析显示肾近端小管严重受损。用阿维菌素或AOAA预处理小鼠对顺铂的肾毒性有保护作用。没有一只经过预处理的动物在献祭前死亡。肾BUN水平和定量组织学分析证实了acivicin和AOAA的保护作用。acivvicin或AOAA未改变肾脏中的铂水平，表明两者均不影响顺铂进入肾脏的摄取。同样，顺铂诱导的体重减轻不会被阿维辛或AOAA改变，这表明体重减轻和肾毒性是通过不同的机制发生的。这些数据支持顺铂的肾毒性是由于GGT和半胱氨酸s缀合β -裂解酶将铂-谷胱甘肽缀合物代谢为强效肾毒素的假设。
Cisplatin is nephrotoxic. The mechanism underlying this organ-specific toxicity is unknown. We hypothesize that cisplatin is metabolized via a gamma-glutamyl transpeptidase (GGT) and cysteine S-conjugate beta-lyase-dependent pathway that has been shown to activate several haloalkenes to nephrotoxins. To test this hypothesis, we inhibited GGT and cysteine S-conjugate beta-lyase in C57BL/6 mice and analyzed the effect of the inhibitors on the nephrotoxicity of cisplatin. GGT was inhibited by pretreating the mice with acivicin. Cysteine S-conjugate beta-lyase was inhibited by aminooxyacetic acid (AOAA). Male C57BL/6 mice were treated with 15 mg/kg cisplatin (i.p.) and sacrificed on day 5. Half the mice treated with cisplatin alone died before sacrifice. The cisplatin-treated mice sacrificed at 5 days had significantly elevated levels of blood urea nitrogen (BUN). Histologic analysis revealed severe damage to the renal proximal tubules. Pretreatment with acivicin or AOAA protected the mice from the nephrotoxicity of cisplatin. None of the pretreated animals died before sacrifice. BUN levels and quantitative histologic analysis of the kidneys confirmed the protective effect of acivicin and AOAA. Platinum levels in the kidneys were not altered by acivicin or AOAA, indicating that neither affected the uptake of cisplatin into the kidney. Likewise, cisplatin-induced weight loss was not altered by acivicin or AOAA, suggesting that weight loss and nephrotoxicity are via distinct mechanisms. These data support the hypothesis that the nephrotoxicity of cisplatin is due to the metabolism of a platinum-glutathione conjugate by GGT and cysteine S-conjugate beta-lyase to a potent nephrotoxin.