Differential toxicity of cis and trans isomers of dichlorodiammineplatinum.
Nephrotoxicity is the dose-limiting toxic effect of cis-dichlorodiammineplatinum (cis-platin) in humans. Its stereoisomer transplatin does not have any toxicity at equimolar concentrations, and it also possesses little antitumor activity. In this study, subcellular localization of both the platinum isomers was examined in the liver and kidney of the mouse 24 hours following the drug administration. Levels of the platinum isomers were measured using flameless atomic absorption. The results showed that higher concentrations of the cis isomer were localized in the liver and kidney, while the concentration of the trans isomer was higher in blood. This indicates that trans isomer is sequestered in the central compartment, whereas cis isomer is distributed in the organs. We also measured metallothionein mRNA and protein levels in both liver and kidney following cisdichlorodiammineplatinum and transdichlorodiammine-platinum treatment to distinguish if the differential toxicity of the two stereoisomers could be related to metallothionein induction. We report here that cisplatin was capable of inducing metallothionein expression in mice in vivo and that there is an inverse relationship between metallothionein expression and the pattern of tissue toxicity induced by the drug.
Singh
G
G
Ontario Cancer Foundation, Hamilton Regional Cancer Centre, Ontario, Canada.
Koropatnick
J
J
D000818:Animals; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013237:Stereoisomerism; D014018:Tissue Distribution
D012333:RNA, Messenger; C034697:transplatin; D008668:Metallothionein; D002945:Cisplatin