Chemical instability and methods for measurement of cisplatin adducts formed by interactions with cysteine and glutathione.
Reactions between cisplatin or its aquated species and L-cysteine (L-cys) or glutathione (GSH) were studied in vitro using liquid chromatography on-line with inductively coupled plasma mass spectrometry (LC-ICPMS) and/or electrospray ionization mass spectrometry (LC-MS) in order to obtain information on the mechanisms occurring in treated patients. Reaction between cisplatin and L-cys yielded initially 4 adducts of which only 2 were stable and detectable after 24 hours incubation; their structures corresponded to bis-platinum cysteinyl adducts. Reaction of cisplatin with GSH proceeded via the formation of at least 11 glutathione-platinum adducts (G1 - G11) which underwent parallel reactions within 24 hours of incubation, probably to form higher molecular weight species. Of the 11 adducts, only 2, G3 and G7, whose structures correspond to [Pt(NH3)2Cl]2(SG) and [Pt(NH3)2OH]2(SG) were still present in the reaction mixture after 24 hours incubation. This study shows that GSH, and to a lesser extent L-cys, incubated with cisplatin in vitro forms unstable and reactive platinum compounds and that LC-ICPMS and LC-MS are 2 complementary techniques suitable for the study of organometallic compounds.
Heudi
O
O
Laboratory of Pharmacology and de Toxicology, University Hospital Center, Angers, France.
Brisset
H
H
Cailleux
A
A
Allain
P
P
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002853:Chromatography, Liquid; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry*; D018736:DNA Adducts; D005978:Glutathione / Q000737:chemistry*; D066298:In Vitro Techniques; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
D000970:Antineoplastic Agents; D018736:DNA Adducts; D005978:Glutathione; D003545:Cysteine; D002945:Cisplatin