Effect of cisplatin on H+ transport by H+ -ATPase and Na+/H+ exchanger in rat renal brush-border membrane.
The effect of the potent anticancer drug cisplatin, cis-diamminedichloroplatinum (II) (CDDP), on H+ -ATPase and Na+/H+ exchanger in rat renal brush-border membrane was examined. To measure H+ transport by vacuolar H+ -ATPase in renal brush-border membrane vesicles, we employed a detergent-dilution procedure, which can reorientate the catalytic domain of H+ -ATPase from an inward-facing configuration to outward-facing one. ATP-driven H+ pump activity decreased markedly in brush-border membrane prepared from rats two days after CDDP administration (5 mg/kg, i.p.). In addition, N-ethylmaleimide and bafilomycin A1 (inhibitors of vacuolar H+ -ATPase)-sensitive ATPase activity also decreased in these rats. The decrease in ATP-driven H+ pump activity was observed even at day 7 after the administration of CDDP. Suppression of ATP-driven H+ pump activity was also observed when brush-border membrane vesicles prepared from normal rats were pretreated with CDDP in vitro. In contrast with H+ -ATPase, the activity of Na+/H+ exchanger, which was determined by measuring acridine orange fluorescence quenching, was not affected by the administration of CDDP. These results provide new insights into CDDP-induced renal tubular dysfunctions, especially such as proximal tubular acidosis and proteinuria.
Shiraishi
Y
Y
Institute of Pharmaceutical Sciences, Faculty of Medicine, Hiroshima University, Japan.
Nagai
J
J
Murakami
T
T
Takano
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001693:Biological Transport, Active / Q000187:drug effects; D020355:Cholates / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects* / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases
D000970:Antineoplastic Agents; D020355:Cholates; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D011522:Protons; D017923:Sodium-Hydrogen Exchangers; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase; D000626:Aminopeptidases; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases; D002945:Cisplatin