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Renal toxicity caused by cisplatinum in glutathione-depleted metallothionein-null mice
1Environmental Health Sciences Division, National Institute for Environmental Studies, 305-0053, Tsukuba, Japan. masahiko@nies.go.jp
Abstract:
To elucidate the protective role of metallothionein (MT) and glutathione (GSH) in renal toxicity caused by cisplatinum (cis-DDP), we examined the sensitivity of GSH-depleted MT-null mice to the renal toxicity of cis-DDP. Blood urea nitrogen and creatinine values in the serum, and histopathological change in the kidney were utilized as indicators of nephrotoxicity caused by cis-DDP. Although cis-DDP exerted renal toxicity in MT-null mice and wild-type mice, the toxicity was more conspicuous in the MT-null mice than in the wild-type mice. Moreover, renal toxicity caused by cis-DDP was enhanced significantly by a decrease in the renal GSH level by buthionine sulfoximine (BSO) pretreatment in both kinds of mice. The cis-DDP-caused nephrotoxicity that was enhanced by BSO-mediated GSH depletion was much more severe in the MT-null mice than in the wild-type mice. However, preadministration of zinc sulfate cancelled the BSO-enhanced, cis-DDP-dependent renal toxicity in the wild-type mice, but not in the MT-null mice. In the present study, we found that MT and GSH play an important, cooperative role in detoxification of severe kidney damage caused by cis-DDP. Moreover, the renal MT preinduced by zinc could protect mice from cis-DDP nephrotoxicity enhanced by GSH depletion.
Insights
Metallothionein (MT) and glutathione (GSH) protect against cisplatin (cis-DDP) kidney damage. MT-null mice showed increased cis-DDP nephrotoxicity, highlighting the cooperative protective roles of MT and GSH in mitigating renal damage.
Area of Science:
- Biochemistry
- Toxicology
- Nephrology
Background:
- Cisplatin (cis-DDP) is a widely used chemotherapy agent with significant nephrotoxic side effects.
- Metallothionein (MT) and glutathione (GSH) are endogenous molecules known to play roles in cellular defense mechanisms against toxic insults.
- The specific, cooperative roles of MT and GSH in mitigating cis-DDP-induced kidney damage require further elucidation.
Purpose of the Study:
- To investigate the protective roles of metallothionein (MT) and glutathione (GSH) in cisplatinum (cis-DDP)-induced nephrotoxicity.
- To determine the sensitivity of MT-null mice, with or without GSH depletion, to cis-DDP-induced renal toxicity.
Main Methods:
- Utilized MT-null and wild-type mice models.
- Administered cis-DDP to induce nephrotoxicity, assessing blood urea nitrogen and creatinine levels.
- Induced GSH depletion using buthionine sulfoximine (BSO) and assessed its impact on cis-DDP nephrotoxicity.
- Investigated the effect of zinc sulfate pre-administration on cis-DDP nephrotoxicity in the presence of GSH depletion.
Main Results:
- Cis-DDP induced significant renal toxicity in both MT-null and wild-type mice, with greater severity observed in MT-null mice.
- BSO-mediated GSH depletion significantly enhanced cis-DDP nephrotoxicity in both mouse types, more pronouncedly in MT-null mice.
- Zinc sulfate administration ameliorated BSO-enhanced cis-DDP nephrotoxicity in wild-type mice but not in MT-null mice.
Conclusions:
- Metallothionein (MT) and glutathione (GSH) play crucial, cooperative roles in detoxifying cis-DDP and protecting against severe kidney damage.
- MT induction by zinc offers protection against cis-DDP nephrotoxicity, particularly when GSH levels are compromised.
- These findings underscore the importance of MT and GSH in managing chemotherapy-induced nephrotoxicity.
