RT Journal Article
SR Electronic
T1 Conversion of melphalan to 4-(glutathionyl)phenylalanine. A novel mechanism for conjugation by glutathione-S-transferases.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 195
OP 199
VO 15
IS 2
A1 D M Dulik
A1 C Fenselau
YR 1987
UL http://dmd.aspetjournals.org/content/15/2/195.abstract
AB 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 degrees 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 evaluated. The formation of GSH adducts of alkylating agents may be a factor in the development of resistance to these drugs.