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Metallomics Vol - 6 Issue - 2

Chemoprotection by d-methionine against cisplatin-induced side-effects: insight from in vitro studies using human plasma

Content Provider	Royal Society of Chemistry (RSC)
Author	Sooriyaarachchi, Melani Narendran, Aru White, Wade M. Gailer, Jürgen
Copyright Year	2014
Abstract	Animal studies have shown that the nephrotoxicity and ototoxicity of the anti-cancer drug cisplatin (CP) can be ameliorated by the co-administration with D-methionine. The molecular mechanisms of this activity, however, are not well understood. Since CP is intravenously administered, the underlying chemistry may involve the interaction of CP-derived Pt-species with D-methionine in the bloodstream. Our previous studies have shown that the chemoprotective agents N-acetyl-L-cysteine and sodium thiosulfate modulate the metabolism of CP in human plasma in vitro, albeit in a different manner. Using a metallomics approach, we show that the incubation of human plasma with D-methionine and CP (molar ratio of 20 : 1) leads to the formation of a Pt–D-methionine complex independent of the order of addition. These results were corroborated by analogous experiments that were carried out using PBS-buffer instead of plasma. In addition, CP and D-methionine were added simultaneously to PBS-buffer and samples were analyzed at certain time intervals by the same metallomics method and LC-ESI-MS over a ∼21 h time period. Whereas the intermediate [Pt(NH3)Cl(D-methionine)]+ species was detected between 1–4 h, only the terminal [Pt(D-methionine)2]+ complex was present 21 h later. Combined, these studies demonstrate that in plasma and at the 20 : 1 D-methionine : CP molar ratio, an early CP hydrolysis product reacts with D-methionine to form a 1 : 1 complex that is followed by the formation of a 2 : 1 compound at a later time point. The formation of these Pt–D-methionine species may therefore play an important role in the processes by which D-methionine protects mammalian organisms against CP-induced toxicities.
Starting Page	532
Ending Page	541
Page Count	10
File Format	HTM / HTML PDF
ISSN	17565901
Volume Number	6
Issue Number	3
Journal	Metallomics
DOI	10.1039/c3mt00238a
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Hydrolysis Ammonia Chemistry Time point Metabolism Nephrotoxicity Sodium thiosulfate Molar concentration Cisplatin Ototoxicity Blood plasma
Content Type	Text
Resource Type	Article
Subject	Chemistry Medicine Metals and Alloys Biochemistry Biomaterials Biophysics

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