Protective role of metallothionein on DNA damage in rat kidney caused by cis-diamminedichloroplatinum.

Abstract

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.