Studies on the formation of reactive intermediates from the antineoplastic agent N,N′Bis(2-chloroethyl)-N-nitrosourea (BCNU) in vitro and in Vivo. Characterization of novel glutathione adducts by ionspray tandem mass spectrometry
✍ Scribed by Margaret R. Davis; Thomas A. Baillie
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 960 KB
- Volume
- 30
- Category
- Article
- ISSN
- 1076-5174
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✦ Synopsis
In a study designed to examine the nature of short-lived, electrophilic intermediates liberated during decomposition of N,N'-bis(2-chloroethyI)-N-nitrosourea (BCNU) in vitro and also on administration of BCNU (140 pmol i.p.) to rats in vivo, both on-line and off-line LC/MS/MS techniques were employed to detect and characterize the corresponding glutathione (GSH) adducts present in incubation media and excreted into bile, respectively. I n vitro, four GSH conjugates were formed and these were identified, on the basis of their product ion spectra, as products of Sand N-carbamoylation and alkylation reactions. Although the relative proportions of these in vitro adducts were found to depend on the molar ratios of GSH and BCNU, the major adduct under all conditions studied proved to be S-( 2-chloroethylcarbamoyl)glutathione (SCG). Analysis of untreated bile samples by means of on-line LC/MSfMS with constant neutral loss (129 u) and precursor ion (m/z 179) scanning techniques again led to the detection of four GSH conjugates, although only one of these (SCG) was common to the group of adducts identified in vitro. All of the GSH conjugates detected in bile represented products of S-carbamoylation, indicating that the alkylating moiety released from BCNU undergoes reactions in vivo with nucleophiles other than GSH.