Glutathione metabolism and glutathione S-conjugate export ATPase (MRP1/GS-X pump) activity in cancer. I. Differential expression in human cancer cell lines.

Mg(2+)-dependent vanadate-sensitive glutathione S-conjugate ATPase (GS-X pump) activity is a common feature of some ATP-binding cassette (ABC) transporters, such as the multidrug resistance-associated protein (MRP1) gene product, that exports biologically active electrophiles after their conjugation with intracellular glutathione (GSH) from normal and cancer cells. Antitumor electrophiles (e.g. naturally occurring cyclopentenone prostaglandins and anticancer chemicals) can be intracellularly conjugated with GSH via a glutathione S-transferase catalyzed reaction and be eliminated through GS-X pumps thus threatening cancer chemotherapeutics. Since different sensitivities to antitumor electrophiles are shown by different cell types, the ability of several human cancer cell lines to produce and export S-(2,4-dinitrophenyl)-glutathione (DNP-SG) conjugate through the GS-X pump, using whole cells and inside-out membrane vesicle preparations, is investigated. Different cancer cell lines exhibited characteristically different GS-X pump activity. In particular, HEp-2 larynx carcinoma cells possess an elevated DNP-SG export rate through the GS-X pump compared with HeLa, K562, U937 or HL-60 cells, which exhibit the lowest activity. The differences in DNP-SG export rates are not due to decreased glutathione S-transferase activity or impaired de novo synthesis of GSH. The findings suggest that the GS-X pump may be involved in the modulation of the biological activity of both naturally occurring electrophiles and anticancer drugs. The differential expression of GS-X pumps may lead to an improved understanding of multidrug resistance and may be exploited in the development of new therapeutic strategies for the treatment of cancer patients.