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Increased Expression of Cytosolic Glutathione S-Transferases in Drug-resistant L5178Y Murine Lymphoblasts: Chemical Selectivity and Molecular Mechanisms¹

Department of Biochemistry and Molecular Biology [G. L. S.], University of Manitoba, Winnipeg, Manitoba, R3E 0W3, and Departments of Pharmacology and Medicine [G. J. G.] and Interdepartmental Division of Oncology [G. J. G.], University of Toronto, Toronto, Ontario, M5G 1L4 Canada

The level of induction of three cytosolic glutathione-S-transferase (GST) classes has been compared in L5178Y murine lymphoblasts resistant to either the quinone-containing compound, hydrolyzed benzoquinone mustard (HBM), or the aromatic alkylating agent aniline mustard (AM). Three established cell lines, L5178Y/HBM2, L5178Y/HBM10, and the partial revertant, L5178Y/HBMR, were 2.5-, 6-, and 2.9-fold resistant to HBM and showed 3-, 11-, and 9-fold increases in GST activity, respectively, relative to the sensitive L5178Y cell line. Western blot analysis of cytosolic proteins showed overexpression of all three cytosolic GST classes , , and µ, with predominance of the class. Northern blot analysis demonstrated corresponding elevations in the steady-state mRNA levels of each GST class. The level of GST-µ and - isoforms correlated more closely with HBM resistance, whereas GST-, the predominant isoform in these cells, paralleled enzyme activity. These findings suggested that other factors such as quinone reductase may contribute to resistance.

The AM-resistant cell line L5178Y/AM was 10-fold resistant to the alkylating agent AM, and GST activity was elevated 3.6-fold relative to the parental L5178Y cell line. Western blot analysis and Northern blot analysis provided evidence of overexpression of all three cytosolic GST classes but with marked predominance of the class. These studies provide evidence that induction of GST isoforms in drug-resistant cells may have both a nonspecific as well as a selective component. The difference in isozyme profile between HBM-and AM-resistant cell lines emphasizes how structural differences, in particular, the nature of the electrophilic signal, may influence the pattern of induction of GST isozymes.

¹ This research was supported by operating grants from the National Cancer Institute of Canada, Bristol-Myers Squibb Pharmaceutical Research Institute, and the Max Shore Cancer Research Fund of the Jewish Foundation of Manitoba.

² To whom requests for reprint should be addressed, at Interdepartmental Division of Oncology, University of Toronto, 92 College Street, Toronto, Ontario, Canada, M5G 1L4.

Received 1/26/93. Accepted 6/ 1/93.