title: Chemoprotection by D-methionine against cisplatin-induced side-effects: insight from in vitro studies using human plasma.
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.
authors: Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada. jgailer@ucalgary.ca.
authors: Melani
authors: M
authors: Sooriyaarachchi
authors: Wade M
authors: WM
authors: White
authors: Aru
authors: A
authors: Narendran
authors: Jürgen
authors: J
authors: Gailer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D002945:Cisplatin / Q000009:adverse effects* / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008715:Methionine / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D020011:Protective Agents; D008715:Methionine; D002945:Cisplatin