Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice.
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.
Ban
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Service Toxicologie Industrielle Expérimentale, INRS, Vandoeuvre, France.
Hettich
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D
Huguet
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N
D000469:Alkaline Phosphatase / Q000378:metabolism; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007555:Isoxazoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D007555:Isoxazoles; D000625:Aminooxyacetic Acid; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008713:Methimazole; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D005978:Glutathione; C006303:acivicin; D011339:Probenecid; D002945:Cisplatin