Glutathione S-transferase (GST) isozymes play a central role in the protection of cells from cytotoxic chemicals and have a putative role in the intrinsic and acquired resistance of tumors to cytotoxic drugs. We have isolated and purified GST isozymes from mouse liver (M. Warholm et al., Biochemistry, 25: 4119–4125, 1986) and analyzed the metabolic products of the reaction of l-phenylalanine mustard (l-PAM) with glutathione in the presence of GST isozymes, using reverse phase high performance liquid chromatography. At pH 6.5, the spontaneous conjugation of l-PAM and glutathione is suppressed and the major product at 60 min is the monochloro, monohydroxyl derivative of l-PAM. Addition of neither class µ nor class π isozymes to the reaction has any effect on the metabolism of l-PAM. Only isozymes of the α GST class catalyze the conjugation of l-PAM with glutathione. In this case, the major metabolite at 1 h is the monochloro, monoglutathionyl conjugate. Increasing the amount of µ or π isozyme in the reaction mixture has no effect on the metabolism of l-PAM, whereas increasing the amount of α isozyme completely supplants hydrolysis with conjugation. Thus, increased levels of class α GST isozyme may represent a specific mechanism whereby cells can acquire resistance to nitrogen mustards.


This work was supported by Grant 5R01-CA16783 from the NIH.

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