Protective role of metallothionein on DNA damage in rat kidney caused by cis-diamminedichloroplatinum.
Cis-diamminedichloroplatinum (cis-DDP) has been used as an anticancer agent but it also causes nephrotoxicity. To study the cis-DDP metabolism and its effects, the induction of metallothioneins and DNA damage caused by cis-DDP were observed. Cis-DDP or trans-DDP was administered to seven-week-old Wistar male rats as three daily injections of 8.0 mg/kg body wt., intraperitoneally. Using the obtained kidneys, gel filtration assay, metal analysis, immunohistochemistry and terminal deoxy transferase-mediated deoxy uracil triphosphate nick end labeling (TUNEL) method were carried out to examine localization of metallothioneins and DNA damage caused by cis-DDP. Platinum (Pt) contents, 26.05+/-12.01 microg/g body wt. and 51.29+/-4.59 microg/g body wt. (average+/-S.E.) were detected in the kidney of rats injected with both cis- and trans-DDP, respectively. Metallothionein was detected in the cortex of the kidney in rats administrated cis-DDP or trans-DDP. The mRNA was also detected in the same region. On the other hand cis-DDP showed induction of DNA damage on the cells in the outer stripe of the outer medulla but trans-DDP did not show any damage. The region-induced DNA damage differed from that induced by metallothioneins. Cis-DDP is suggested to be mainly trapped at the proximal tubules by metallothioneins, and the rest of cis-DDP induces DNA damage at the outer stripe of the outer medulla. Metallothioneins are considered to contribute to the protection against cis-DDP in the rat cortex.
Hosokawa
O
O
Research Division for Higher Education, Center for Research and Development in Higher Education, Hokkaido University, Sapporo, Japan. thoso@high.hokudai.ac.jp
Okabe
M
M
Saito
S
S
Saito
T
T
Kurasaki
M
M
D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D003300:Copper / Q000032:analysis; D004249:DNA Damage / Q000187:drug effects*; D006651:Histocytochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000737:chemistry; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D018613:Microscopy, Confocal; D010984:Platinum / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015032:Zinc / Q000032:analysis
D012333:RNA, Messenger; C034697:transplatin; D010984:Platinum; D003300:Copper; D008668:Metallothionein; D015032:Zinc; D002945:Cisplatin