Glutathione conjugation with phosphoramide mustard and cyclophosphamide: A mechanistic study using tandem mass spectrometry

Z. M. Yuan, P. B. Smith, R. B. Brundrett, M. Colvin, C. Fenselau

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

The conjugations of cyclophosphamide and of phosphoramide mustard with glutathione are shown to be catalyzed by hepatic cytosolic glutathione-S-transferases. Cyclophosphamide conjugation is also catalyzed by microsomal glutathione-S-transferases, both in intact microsomes and after solubilization and immobilization. Deuterium isotope labels are used to test whether chloride is directly displaced by glutathione in the enzyme-catalyzed conjugations, or whether conjugation takes place via symmetrical cyclic aziridinium ions. Tandem mass spectrometry with high energy collisional activation is shown to provide reliable analysis of the isotope-labeling patterns in the conjugated products. This experiment leads to the conclusion that the aziridinium ion is opened in the conjugation of phosphoramide mustard in both the enzyme-catalyzed and the chemical reactions. Cyclophosphamide, on the other hand, is shown to be conjugated through direct displacement of chloride.

Original languageEnglish (US)
Pages (from-to)625-629
Number of pages5
JournalDrug Metabolism and Disposition
Volume19
Issue number3
StatePublished - 1991

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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