The inhibition of renal ATPase by cisplatin and some biotransformation products.
The anti-tumour drug cisplatin is a potent nephrotoxic agent. Renal Na+/K+-activated and Mg2+-activated ATPases are shown to be equally sensitive to cisplatin inhibition in vitro. An aged solution of cisplatin, containing hydrolysis products, is a thousand times more inhibitory to ATPase (ID50 8.0 X 10(-7) M) than freshly made cisplatin solutions (ID50 6.5 X 10(-4) M). Chloride ion concentrations of 0-150 mM in the assay mixtures do not affect either the extent of inhibition of ATPase by cisplatin or the time required for inhibition to develop. We conclude that cisplatin reacts directly with ATPase rather than that a hydrolysis product is responsible for the inhibition. Various amino acid complexes with cisplatin were tested for their ability to inhibit ATPase. Cysteine/cisplatin in a mole ratio of 1 : 1 is completely ineffective. Mono-substituted methionine/cisplatin is more inhibitory than cisplatin alone but di-substituted methionine/cisplatin is less effective. The reason for these observations and their significance to nephrotoxicity are discussed.
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D017301:Ca(2+) Mg(2+)-ATPase; D002712:Chlorides / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D003545:Cysteine / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008715:Methionine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D002712:Chlorides; D008715:Methionine; D000251:Adenosine Triphosphatases; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D003545:Cysteine; D002945:Cisplatin