Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice

Abstract

Male Swiss OF1 mice were injected subcutaneously with 20 mg/kg of cis-platinum (II) diamine dichloride (cis-platin). Examination of cryostat kidney sections stained for alkaline phosphatase (APP) revealed damage to about 10, 20, 40 and 50% of the proximal tubules after 7, 24, 48 and 72 h, respectively. Pretreatment with the glutathione synthesis inhibitor, buthionine sulfoximine (BSO), (i.p. 3 mmol/kg) potentiated the tubule damage of cis-platin. In contrast, pretreatment with organic anion transport inhibitor probenecid (i.p. 3 x 0.75 mmol/kg) reduced the number of damaged tubules by approximately 80% at 72 h after cis-platin injection. Pretreatment with the gamma-glutamyltranspeptidase (gamma-GT) inactivator acivicin (AT-125, 50 mg/kg p.o., plus 50 mg/kg i.p.) failed to prevent cis-platin induced renal toxicity. Pretreatment with the beta-lyase inactivator aminooxyacetic acid (AOAA, 2 x 100 mg/kg p.o.) and with the renal cysteine conjugate S-oxidase inhibitor methimazole (40 mg/kg i.p.) reduced the number of damaged tubules by approximately 40% and 75%, respectively in mice treated with cis-platin. The results suggest that the platinum-sulfhydryl group complexes formed are taken up by the kidney cells through an organic anion transport mechanism which is probenecid-sensitive. In the cells these complexes are stable for several hours, depending on the intracellular glutathione (GSH) level, and gradually undergo transformation to reactive metabolite(s) by renal intracellular beta-lyase and S-oxidase.