Covalent binding of cisplatin impairs the function of Na⁺/K⁺-ATPase by binding to its cytoplasmic part

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• 作者：Miroslav Hulič ; iak^a ; Jan Vacek^b ; Marek Š ; ebela^c ; Eva Orolinová ; ^b ; Joanna Znaleziona^b ; Marika Havlí ; ková ; ^a ; Martin Kubala^a ; ^{mkubala@prfnw.upol.cz}
• 关键词：Cisplatin ; Nephrotoxicity ; Na+ ; K+-ATPase ; Sodium pump ; Cysteine
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 June, 2012
• 卷：83
• 期：11
• 页码：1507-1513
• 文件大小：809 K

摘要

This study was aimed at verifying the hypothesis that acute kidney failure accompanying cisplatin administration in the cancer therapy could be due to cisplatin interaction with the cytoplasmic part of Na⁺/K⁺-ATPase. Our results demonstrated that cisplatin-binding caused inhibition of Na⁺/K⁺-ATPase, in contrast to other platinated chemotherapeutics such as carboplatin and oxaliplatin, which are known to be much less nephrotoxic. To acquire more detailed structural information, we performed a series of experiments with the isolated large cytoplasmic segment connecting transmembrane helices 4 and 5 (C45 loop) of Na⁺/K⁺-ATPase. Electrochemistry showed that cisplatin is bound to the cysteine residues of the C45 loop, mass spectrometry revealed a modification of the C45 peptide fragment GSHMASLEAVETLGSTSTICSDK, which contains the conserved phosphorylated residue Asp369. Hence, we hypothesize that binding of cisplatin to Cys367 can cause sterical obstruction during the phosphorylation or dephosphorylation step of the Na⁺/K⁺-ATPase catalytic cycle.