ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump
Open accessAbstract
We have previously shown that the multidrug resistance protein (MRP) mediates the ATP-dependent membrane transport of the endogenous glutathione conjugate leukotriene C4 (LTC4) and of structurally related anionic conjugates of lipophilic compounds [Jedlitschky, Leier, Buchholz, Center and Keppler (1994) Cancer Res. 54, 4833–4836; Leier, Jedlitschky, Buchholz, Cole, Deeley and Keppler (1994) J. Biol. Chem. 269, 27807–27810]. We demonstrate in the present study that MRP also mediates the ATP-dependent transport of GSSG, as shown in membrane vesicles from human leukaemia cells overexpressing MRP (HL60/ADR cells) or HeLa cells transfected with an MRP expression vector (HeLa T5 cells) in comparison with the respective parental or control cells. The Km value for ATP-dependent transport of GSSG was 93±26 μM (mean value±S.D., n = 5) in membrane vesicles from HeLa T5 cells. GSH, at a concentration of 100 μM, was not a substrate for any significant ATP-dependent MRP-mediated transport. The transport of GSSG was competitively inhibited by LTC4, by the leukotriene D4 receptor antagonist 3-([{3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl}-{(3-dimethylamino-3-oxopropyl)-thio}-methyl]thio)propanoic acid (MK571) and by S-decylglutathione, with Ki values of 0.3, 0.6 and 0.7 μM respectively. These studies identify MRP as the membrane glycoprotein which mediates the ATP-dependent export of GSSG from these cells.
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The KM-values for Mrp1-mediated export of GSSG are in the micromolar range.
“KM‐values for the Mrp1‐mediated export of GSSG and the GSH‐conjugate glutathione‐bimane (GS‐B) are in the micromolar and nanomolar range (Homma et al. 1999; Leier et al. 1996), respectively.”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Leier et al. 1996
The KM-values for Mrp1-mediated export of the GSH-conjugate glutathione-bimane (GS-B) are in the nanomolar range.
“KM‐values for the Mrp1‐mediated export of GSSG and the GSH‐conjugate glutathione‐bimane (GS‐B) are in the micromolar and nanomolar range (Homma et al. 1999; Leier et al. 1996), respectively.”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Leier et al. 1996
The kinetic-characterization section reports micromolar Kₘ values for GSSG transport, and the Discussion gives a nanomolar Kₘ for leukotriene C₄, not glutathione-bimane. Searches for glutathione-bimane, GS-B, and monochlorobimane found no passage in our copy reporting its transport Kₘ. (LLM, conf=0.76)
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Cites
Overexpression of a Transporter Gene in a Multidrug-Resistant Human Lung Cancer Cell Line
Cole, S. P. C., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., Stewart, A. J., Kurz, E. U., Duncan, A. M. V., & Deeley, R. G. (1992) · Science · doi:10.1126/science.1360704 · Cited by 3,037 · see citing works
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- Kondo, T., Dale, G. L. and Beutler, E. (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 6359-6362
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Deeley, R. G., Westlake, C., & Cole, S. P. C. (2006) · Physiological Reviews · doi:10.1152/physrev.00035.2005 · Cited by 761 · see citing works
Self-citationToxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters
Leslie, E. (2001) · Toxicology · doi:10.1016/s0300-483x(01)00454-1 · Cited by 376 · see citing works
Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases
Chen, Z., & Tiwari, A. K. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2011.08235.x · Cited by 274 · see citing works
Hanssen, K. M., Haber, M., & Fletcher, J. I. (2021) · Drug Resistance Updates · doi:10.1016/j.drup.2021.100795 · Cited by 102 · see citing works
Glutathione Metabolism of the Brain—The Role of Astrocytes
Dringen, R., & Arend, C. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70073 · Cited by 46 · see citing works
- Authors
- LEIER, I., JEDLITSCHKY, G., BUCHHOLZ, U., CENTER, M., COLE, S. P. C., DEELEY, R. G., & KEPPLER, D.
- Affiliations
- German Cancer Research Center (DE)
- Division of Biology, Kansas State University, Manhattan, KS 66506, U.S.A.
- Kansas State University (US)
- Queen's University (CA)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1996-03-01
- Volume
- 314
- Issue
- 2
- Pages
- 433-437
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1217068
- OpenAlex
- W2290695793
- Cited by
- 291
- References
- 1
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2021: 5 · 2020: 7 · 2019: 3 · 2018: 7 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 4 · 2013: 7 · 2012: 9
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- multidrug resistance protein, MRP, glutathione disulfide, leukotriene C4, MK571, leukotriene D4 receptor antagonist, competitive inhibition
- MeSH terms
- Adenosine Triphosphate, Bile Canaliculi, Biological Transport, Cell Membrane, Glutathione, HeLa Cells, Humans, Tritium, Tumor Cells, Cultured, Leukotriene C4, ATP-Binding Cassette Transporters, Glutathione Disulfide, ATP-Binding Cassette, Sub-Family C Proteins
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