Protective role of metallothionein in renal toxicity of cisplatinum.
To elucidate the protective role of metallothionein (MT) in the prevention of cisplatinum (cis-DDP) toxicity, we investigated the lethal and renal toxicities caused by cis-DDP in MT-null transgenic mice in comparison with wild-type control mice, and examined the effect of pretreatment with bismuth nitrate or zinc sulfate on the cis-DDP nephrotoxicity. The MT-null mice were of mixed 129 Ola and C57BL/6 genetic background. Since no differences in cis-DDP nephrotoxicity were observed between these strains, C57BL/6J mice were used as the wild-type control. The basal MT levels in the kidneys were negligible in the MT-null mice and 2.93 +/- 0.77 micrograms/g tissue in the C57BL/6J mice. In terms of both the lethal and renal toxicities of cis-DDP, MT-null mice were far more sensitive than C57BL/6J mice. Preinduction of renal MT synthesis by administration of bismuth nitrate or zinc sulfate protected C57BL/6J mice from cis-DDP nephrotoxicity. In the case of MT-null mice, however, renal MT could not be induced by pretreatment with these metal compounds, and renal toxicity of cis-DDP was not prevented by this pretreatment. These results suggest that MT is an important factor with the potential to suppress the development of cis-DDP toxicity.
Satoh
M
M
Environmental Health Sciences Division, National Institute for Environmental Studies, Ibaraki, Japan. masahiko@nies.go.jp
Aoki
Y
Y
Tohyama
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001729:Bismuth / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009566:Nitrates / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000032:analysis; D019287:Zinc Sulfate / Q000494:pharmacology
D000970:Antineoplastic Agents; D009566:Nitrates; D013438:Sulfhydryl Compounds; C065545:bismuth nitrate; D019287:Zinc Sulfate; D008668:Metallothionein; D003404:Creatinine; D002945:Cisplatin; D001729:Bismuth