顺铂对 P 型 ATP 酶转运活性的影响。

Effect of cisplatin on the transport activity of P-type ATPases.

机构信息

Department of Chemistry "Ugo Schiff", University of Florence, 50019 Sesto Fiorentino, Italy.

出版信息

Metallomics. 2017 Jul 19;9(7):960-968. doi: 10.1039/c7mt00100b.

Abstract

Cisplatin (cis-diamminedichlorido-Pt(ii)) is extensively used as a chemotherapeutic agent against various types of tumors. However, cisplatin administration causes serious side effects, including nephrotoxicity, ototoxicity and neurotoxicity. It has been shown that cisplatin can interact with P-type ATPases, e.g., Cu-ATPases (ATP7A and ATP7B) and Na,K-ATPase. Cisplatin-induced inhibition of Na,K-ATPase has been related to the nephrotoxic effect of the drug. To investigate the inhibitory effects of cisplatin on the pumping activity of P-type ATPases, electrical measurements were performed on sarcoplasmic reticulum Ca-ATPase (SERCA) and Na,K-ATPase embedded in vesicles/membrane fragments adsorbed on a solid-supported membrane. We found that cisplatin inhibits SERCA and Na,K-ATPase only when administered without a physiological reducing agent (GSH); in contrast, inhibition was also observed in the case of Cu-ATPases in the presence of 1 mM GSH. Our results indicate that cisplatin is a much stronger inhibitor of SERCA (with an IC value of 1.3 μM) than of Na,K-ATPase (with an IC value of 11.1 μM); moreover, cisplatin inhibition of Na,K-ATPase is reversible, whereas it is irreversible in the case of SERCA. In the absence of a physiological substrate, while Cu-ATPases are able to translocate cisplatin, SERCA and Na,K-ATPase do not perform ATP-dependent cisplatin displacement.

摘要

顺铂（cis-diamminedichlorido-Pt(ii)）被广泛用作治疗各种类型肿瘤的化疗药物。然而，顺铂给药会引起严重的副作用，包括肾毒性、耳毒性和神经毒性。已经表明，顺铂可以与 P 型 ATP 酶（例如，Cu-ATPases（ATP7A 和 ATP7B）和 Na，K-ATPase）相互作用。顺铂诱导的 Na，K-ATP 酶抑制与药物的肾毒性作用有关。为了研究顺铂对 P 型 ATP 酶泵送活性的抑制作用，在嵌入囊泡/膜片段的肌浆网 Ca-ATP 酶（SERCA）和 Na，K-ATP 酶上进行了电测量，这些囊泡/膜片段吸附在固体支撑膜上。我们发现，只有在没有生理还原剂（GSH）的情况下，顺铂才会抑制 SERCA 和 Na，K-ATP 酶；相比之下，在存在 1mM GSH 的情况下，Cu-ATPases 也观察到了抑制作用。我们的结果表明，顺铂是 SERCA（IC 值为 1.3μM）的抑制剂比 Na，K-ATP 酶（IC 值为 11.1μM）更强；此外，顺铂抑制 Na，K-ATP 酶是可逆的，而在 SERCA 的情况下则是不可逆的。在没有生理底物的情况下，虽然 Cu-ATPases 能够转运顺铂，但 SERCA 和 Na，K-ATP 酶不能进行 ATP 依赖性顺铂置换。