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Glutathione metabolism and glutathione S‐conjugate export ATPase (MRP1/GS‐X pump) activity in cancer
Author(s) -
de Bittencourt Paulo Homem,
Senna Sueli M.,
Vidor Ana C.,
Miyasaka Célio K.,
Curi Rui,
Williams John F.
Publication year - 1998
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1080/15216549800203462
Subject(s) - glutathione , conjugate , chemistry , metabolism , atpase , biochemistry , enzyme , mathematical analysis , mathematics
Abstract A severe complication in late‐stage cancer patients is host immunosuppression. It is suggested that overproduction of the highly cytostatic and cytotoxic antiproliferative cyclopentenone prostaglandins (CP‐PGs) within the plasma of cancer‐bearing subjects may contribute to immunosuppression. Lymphoid tissues of Walker 256 tumor‐bearing rats accumulate large amounts of CP‐PGs while the tumor tissue itself does not. Moreover, tumor cells may present differential sensitivity to CP‐PGs due to the expression of the multidrug resistance‐associated protein (MRP1) gene product which shows a Mg2+‐dependent vanadate‐sensitive glutathione S‐conjugate export ATPase (GS‐X pump) activity that extrudes CP‐PGs from cells as glutathione S‐conjugates. In this study, the possibility that deficient GS‐X pump activity in immune cells that may be involved in the accumulation of CP‐PGs is investigated. Rat lymph node lymphocytes do not exhibit any notable activity even when mitogen‐stimulated. Conversely, although rat peritoneal resident (quiescent) or thioglycollate‐stimulated (inflammatory) macrophages exhibit low GS‐X pump activity, Bacillus Calmette‐Guérin (BCG)‐activated macrophages show a notable rise in the activity of the ATPase, suggesting that the cellular activation state may modulate GS‐X pump activity/expression and that, under appropriate stimuli (e.g. during immune response) macrophages may provide a self‐defense against etectrophilic CP‐PGs by forming GS‐conjugates that can be extruded from cells through the GS‐X pump. ras oncogene expression may be linked with MRP1/GS‐X pump expression/activity, since C2C12 promyoblasts transformed by v‐H‐ras transfection doubled GS‐X pump activity. These results support the proposition that the accumulation of CP‐PGs and the immunosuppression of tumor‐bearing subjects may be attributed to a lack of GS‐X pump activity/expression in lymphocytes.