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Specificity of Isozymes of Murine Hepatic Glutathione S-Transferase for the Conjugation of Glutathione with L-Phenylalanine Mustard¹

The Laboratory of Pharmacology and Experimental Therapeutics, The Johns Hopkins Oncology Center, Baltimore, Maryland 21205

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 isozymes to the reaction has any effect on the metabolism of L-PAM. Only isozymes of the 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 isozyme in the reaction mixture has no effect on the metabolism of L-PAM, whereas increasing the amount of isozyme completely supplants hydrolysis with conjugation. Thus, increased levels of class GST isozyme may represent a specific mechanism whereby cells can acquire resistance to nitrogen mustards.

¹ This work was supported by Grant 5R01-CA16783 from the NIH.

² To whom requests for reprints should be addressed.

Received 3/12/90. Accepted 2/19/91.

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