Nechay B R, Neldon S L
Cancer Treat Rep. 1984 Sep;68(9):1135-41.
Cisplatin and chloroplatinic acid were examined for in vitro inhibition of human renal microsomal adenosine triphosphatases activated by Na+ + K+ + Mg2+, Mg2+, and Ca2+. The concentrations of cisplatin to inhibit 50% of activity (I50) were approximately 7 X 10(-4) M for all enzymes studied; I50s of chloroplatinic acid were on the order of 10(-5) M for Na+ + K+ + Mg2+ ATPase and Ca2+ ATPase and 10(-7) M for Mg2+ ATPase in the presence of Na+ + K+ + ouabain. Inhibition of Na+ + K+ + Mg2+ ATPase by cisplatin or chloroplatinic acid was reversible and was not altered by varying Na+, K+, or Mg2+ concentrations; ATP or MgATP increased inhibition by cisplatin but not by chloroplatinic acid; acidic pH of 6.8 lowered inhibition by chloroplatinic acid but not by cisplatin. Cysteine, glutathione (-SH reagents), and ascorbic acid greatly reduced inhibition of all enzymes studied by chloroplatinic acid; in the case of cisplatin, -SH reagents had only a minimal protective effect but ascorbic acid somewhat increased inhibition. Methionine greatly increased inhibition by cisplatin but provided minimal protection in the case of chloroplatinic acid. In view of the hypothesis that inhibition of renal Na+ + K+ ATPase may be associated with tubular damage, the inhibition of Na+ + K+ ATPase may be relevant to the mechanism of platinum toxicity.
研究了顺铂和氯铂酸对由Na⁺ + K⁺ + Mg²⁺、Mg²⁺和Ca²⁺激活的人肾微粒体三磷酸腺苷酶的体外抑制作用。对于所研究的所有酶，顺铂抑制50%活性的浓度（I50）约为7×10⁻⁴ M；在存在Na⁺ + K⁺ + 哇巴因的情况下，氯铂酸对Na⁺ + K⁺ + Mg²⁺ ATP酶和Ca²⁺ ATP酶的I50约为10⁻⁵ M，对Mg²⁺ ATP酶的I50约为10⁻⁷ M。顺铂或氯铂酸对Na⁺ + K⁺ + Mg²⁺ ATP酶的抑制作用是可逆的，并且不会因改变Na⁺、K⁺或Mg²⁺的浓度而改变；ATP或MgATP会增强顺铂的抑制作用，但不会增强氯铂酸的抑制作用；pH 6.8的酸性环境会降低氯铂酸的抑制作用，但不会降低顺铂的抑制作用。半胱氨酸、谷胱甘肽（-SH试剂）和抗坏血酸能大大降低氯铂酸对所研究的所有酶的抑制作用；就顺铂而言，-SH试剂只有最小的保护作用，但抗坏血酸会在一定程度上增强抑制作用。甲硫氨酸会大大增强顺铂的抑制作用，但对氯铂酸的保护作用极小。鉴于肾Na⁺ + K⁺ ATP酶的抑制可能与肾小管损伤有关这一假说，Na⁺ + K⁺ ATP酶的抑制可能与铂毒性机制相关。
