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.