Renal toxicity caused by cisplatinum in glutathione-depleted metallothionein-null mice.
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.
Satoh
M
M
Environmental Health Sciences Division, National Institute for Environmental Studies, 305-0053, Tsukuba, Japan. masahiko@nies.go.jp
Shimada
A
A
Zhang
B
B
Tohyama
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects* / Q000473:pathology; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
D000970:Antineoplastic Agents; D008668:Metallothionein; D005978:Glutathione; D002945:Cisplatin