CONVERSION OF MELPHALAN TO 4-(GLUTATHIONYL)PHENYLALANINE - A NOVEL MECHANISM FOR CONJUGATION BY GLUTATHIONE-S-TRANSFERASES

  • 1 March 1987
    • journal article
    • research article
    • Vol. 15  (2) , 195-199
Abstract
One of the conjugates of melphalan, characterized following incubation with glutathione (GSH) and immobilized microsomal glutathione-S-transferases, has been identified as 4-(glutathionyl)phenylalanine. This conjugate is formed by displacement of the mustard moiety. The structure was confirmed by reaction of the corresponding 4-halophenylalanines with GSH as well as by TLC, HPLC, and FAB mass spectrometry. Evidence is presented here to support the hypothesis that this novel reaction occurs via a cyclic aziridinium ion. To test this proposed mechanism, N,N-dimethyl-p-toluidine and its corresponding quaternary ammonium iodide salt were incubated with GSH in the presence of immobilized glutathione-S-transferases at 37.degree. C for 1 hr at pH 7.4. The tertiary amine did not react, whereas the quaternary compound produced 4-(glutathionyl)toluene. The effect of ring substituent requirements for the reaction was evaluted. The formation of GSH adducts of alkylating agents may be a factor in the development of resistance to these drugs.

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