Cisplatin-induced毒性与铂沉积在老鼠体内肾脏线粒体和选择性失活LLC-PK1 alpha-ketoglutarate脱氢酶复杂的细胞。

文章的细节

引用

复制到剪贴板

张L,库珀AJ, Krasnikov BF,徐H,小家伙P,平托JT,吉布森通用电气、Hanigan MH

Cisplatin-induced毒性与铂沉积在老鼠体内肾脏线粒体和选择性失活LLC-PK1 alpha-ketoglutarate脱氢酶复杂的细胞。

生物化学。2006年7月25日,45 (29):8959 - 71。

PubMed ID

16846239 (在PubMed

]

文摘

抗癌药物顺铂肾毒性和神经毒性。先前的数据支持这一假说,顺铂是bioactivated nephrotoxicant。拟议中的bioactivation的最后一步是形成platinum-cysteine S-conjugate后跟一个5 '磷酸吡哆醛(PLP)端依赖半胱氨酸S-conjugate beta-lyase反应。这个反应会生成丙酮酸,铵和高活性铂(Pt)硫醇化合物结合蛋白质的体内。在这部作品中,细胞的位置和身份PLP-dependent半胱氨酸S-conjugate beta-lyase进行调查。Pt显示绑定到蛋白质cisplatin-treated小鼠的肾脏。Pt-bound蛋白质的浓度在胞质中线粒体的分数更高的分数。治疗的小鼠aminooxyacetic酸(AOAA PLP酶抑制剂),此前被证明块顺铂肾毒性,减少Pt线粒体蛋白质的约束力,但没有影响Pt绑定在胞质蛋白的量分数。这些数据表明,线粒体酶催化PLP-dependent半胱氨酸S-conjugate beta-lyase反应。PLP-dependent线粒体天冬氨酸转氨酶(mitAspAT)是线粒体酶,催化卤代烯烃的半胱氨酸S-conjugates beta-elimination反应。 We reasoned that the enzyme might also catalyze a beta-lyase reaction with the cisplatin-cysteine S-conjugate. In this study, mitAspAT was stably overexpressed in LLC-PK(1) cells. Cisplatin was significantly more toxic in confluent monolayers of LLC-PK(1) cells that overexpressed mitAspAT than in control cells containing vector alone. AOAA completely blocked the cisplatin toxicity in confluent mitAspAT-transfected cells. The Pt-thiol compound could rapidly bind proteins and inactivate enzymes in close proximity of the PLP-dependent cysteine S-conjugate beta-lyase. Treatment with 50 or 100 microM cisplatin for 3 h, followed by removal of cisplatin from the medium for 24 h, resulted in a pronounced loss of alpha-ketoglutarate dehydrogenase complex (KGDHC) activity in both mitAspAT-transfected cells and control cells. Exposure to 100 microM cisplatin resulted in a significantly greater loss of KGDHC activity in the cells overexpressing mitAspAT than in control cells. Aconitase activity was diminished in both cell types, but only at the higher level of exposure to cisplatin. AspAT activity was also significantly decreased by cisplatin treatment. By contrast, several other enzymes (both cytosolic and mitochondrial) involved in energy/amino acid metabolism were not significantly affected by cisplatin treatment in the LLC-PK(1) cells, whether or not mitAspAT was overexpressed. The susceptibility of KGDHC and aconitase to inactivation in kidney cells exposed to cisplatin metabolites may be due to the proximity of mitAspAT to KGDHC and aconitase in mitochondria. These findings support the hypothesis that a mitochondrial cysteine S-conjugate beta-lyase converts the cisplatin-cysteine S-conjugate to a toxicant, and the data are consistent with the hypothesis that mitAspAT plays a role in the bioactivation of cisplatin.

DrugBank数据引用了这篇文章

药物靶点

药物	目标	类	生物	药理作用	行动
磷酸吡哆醛	犬尿氨酸——氧化戊二酸氨基转移酶1	蛋白质	人类	未知的	代数余子式	细节