Characteristics of inhibition of human renal adenosine triphosphatases by cisplatin and chloroplatinic acid.
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.
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D001205:Ascorbic Acid / Q000494:pharmacology; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003545:Cysteine / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008715:Methionine / Q000494:pharmacology; D010984:Platinum / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017671:Platinum Compounds; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D017671:Platinum Compounds; C002999:chloroplatinic acid; D010984:Platinum; D008715:Methionine; D000251:Adenosine Triphosphatases; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D003545:Cysteine; D001205:Ascorbic Acid; D002945:Cisplatin