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Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice
1Service Toxicologie Industrielle Expérimentale, INRS, Vandoeuvre, France.
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.
Insights
Cisplatin causes kidney tubule damage in mice, potentiated by glutathione synthesis inhibition. Probenecid, an organic anion transport inhibitor, significantly reduced this damage, suggesting a probenecid-sensitive uptake mechanism for platinum-sulfhydryl complexes.
Area of Science:
- Nephrology
- Toxicology
- Molecular Biology
Background:
- Cisplatin is a widely used chemotherapy agent with known nephrotoxicity.
- The exact mechanisms underlying cisplatin-induced kidney damage are not fully understood.
- Investigating cellular pathways involved in cisplatin uptake and metabolism is crucial for mitigating its side effects.
Purpose of the Study:
- To elucidate the mechanisms of cisplatin nephrotoxicity in mice.
- To investigate the role of organic anion transport and intracellular metabolism in cisplatin-induced kidney damage.
- To evaluate potential protective strategies against cisplatin nephrotoxicity.
Main Methods:
- Male Swiss OF1 mice were administered cisplatin (20 mg/kg).
- Kidney sections were examined for proximal tubule damage using alkaline phosphatase staining.
- Mice were pretreated with inhibitors of glutathione synthesis (BSO), organic anion transport (probenecid), gamma-glutamyltranspeptidase (acivicin), beta-lyase (AOAA), and S-oxidase (methimazole).
Main Results:
- Cisplatin induced progressive proximal tubule damage, reaching 50% at 72 hours.
- Buthionine sulfoximine potentiated cisplatin nephrotoxicity.
- Probenecid pretreatment reduced cisplatin-induced tubule damage by approximately 80%.
- Acivicin did not prevent toxicity, while AOAA and methimazole offered partial protection.
- Results suggest probenecid-sensitive organic anion transport mediates platinum-sulfhydryl complex uptake.
Conclusions:
- Cisplatin-induced nephrotoxicity involves the uptake of platinum-sulfhydryl complexes via a probenecid-sensitive organic anion transport system.
- Intracellular metabolism by beta-lyase and S-oxidase contributes to the formation of reactive metabolites.
- Targeting organic anion transport may offer a strategy to reduce cisplatin nephrotoxicity.