The effect of cisplatin on renal ATPase activity in vivo and in vitro.
The effect of cisplatin on ATPase activity was determined in vitro and in vivo to investigate the correlation between nephrotoxicity and the inhibition of ATPase activity by cisplatin. Purified Na,K-ATPase was preincubated for 0-240 min with cisplatin at concentrations of 50-800 microM in vitro before the determination of enzyme activity. Although ATPase activity was reduced by cisplatin, either a high concentration of cisplatin (280 microM) or a long period of preincubation (160 min) with cisplatin was required to obtain 50% inhibition of ATPase activity. Similar in vitro experiments using kidney homogenate from female Sprague-Dawley rats instead of purified Na,K-ATPase were performed. Activity of Na,K-ATPase in rat kidney homogenate was inhibited by 50% after 110 min preincubation with 800 microM cisplatin or 160 min preincubation with 400 microM cisplatin. Female Sprague-Dawley rats were given 5, 7 or 10 mg/kg of cisplatin IV and BUN level, ATPase activity and Pt concentration in kidney homogenate were evaluated 1 h, 6 h, 1 day, 3 days, and 5 days after cisplatin injection. In rats given 10 mg/kg cisplatin a significant increase of BUN was observed on days 1, 3, and 5. In rats treated with 5 or 7 mg/kg of cisplatin BUN was increased on days 3 and 5. Normal ATPase activity, however, was preserved until day 3 at all doses. The highest concentration of Pt observed in kidney tissue was 19.3 micrograms/g tissue. This value was insufficient to inhibit ATPase activity significantly in vitro. Thus, it seems unlikely that the inhibition of ATPase activity is the cause of nephrotoxicity, although cisplatin can affect ATPase activity.
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D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D017301:Ca(2+) Mg(2+)-ATPase; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D010984:Platinum / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D010984:Platinum; D000251:Adenosine Triphosphatases; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D002945:Cisplatin