The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide from brain astrocytes
Abstract
Astrocytes play an important role in the glutathione (GSH) metabolism of the brain. To test for an involvement of multidrug resistance protein (Mrp) 1 and 5 in the release of GSH and glutathione disulfide (GSSG) from astrocytes, we used astrocyte cultures from wild‐type, Mrp1‐deficient [Mrp1(–/–)] and Mrp5‐deficient [Mrp5(–/–)] mice. During incubation of wild‐type or Mrp5(–/–) astrocytes, GSH accumulated in the medium at a rate of about 3 nmol/(h.mg), whereas the export of GSH from Mrp1(–/–) astrocytes was only one‐third of that. In addition, Mrp1(–/–) astrocytes had a 50% higher specific GSH content than wild‐type or Mrp5(–/–) cells. The presence of 50 μ m of the Mrp inhibitor MK571 inhibited the rate of GSH release from wild‐type and Mrp5(–/–) astrocytes by 60%, but stimulated at the low concentration of 1 μ m GSH release by 40%. In contrast, both concentrations of MK571 did not affect GSH export from Mrp1(–/–) astrocytes. Moreover, in contrast to wild‐type and Mrp5(–/–) cells, GSSG export during H 2 O 2 stress was not observed for Mrp1(–/–) astrocytes. These data demonstrate that in astrocytes Mrp1 mediates 60% of the GSH export, that Mrp1 is exclusively responsible for GSSG export and that Mrp5 does not contribute to these transport processes.
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GSH, GSSG, and GS-B are exported by Mrp1, as demonstrated by the strong impairment of the respective export process by inhibition or knockout of Mrp1.
“Although GSH, GSSG, and GS‐B are exported by Mrp1, as demonstrated by the strong impairment of the respective export process by inhibition or knockout of Mrp1 (Hirrlinger et al. 2002b; Minich et al. 2006)”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Minich et al. 2006
GSH export from murine astrocytes is primarily mediated by Mrp1.
“The GSH export from murine astrocytes is primarily mediated by Mrp1 (Hirrlinger et al. 2002b; Minich et al. 2006)”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Minich et al. 2006
Cultured astrocytes are able to efficiently export GSSG and GSH-conjugates via Mrp1 under conditions that induce oxidative stress and after application of given electrophiles.
“cultured astrocytes are able to efficiently export GSSG and GSH‐conjugates via Mrp1 (Figure 2) under conditions that induce oxidative stress (Arend et al. 2024; Hirrlinger et al. 2001; Minich et al. 2006; Raabe et al. 2019;) and after the application of given electrophiles (Arend et al. 2024; Dringen et al. 2015; Raabe et al. 2019; Waak and Dringen 2006), respectively.”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Minich et al. 2006
GSH is exported from astrocytes by the multidrug resistance protein 1 (Mrp1).
“The GSH export from murine astrocytes is primarily mediated by Mrp1 (Hirrlinger et al. 2002b; Minich et al. 2006), which belongs to the ATP binding‐cassette (ABC) protein family of ATP‐driven export pumps (Cole 2014; Huang and Ecker 2023; Wang et al. 2021).”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Minich et al. 2006
The export of GSH from astrocytes is mainly mediated by the ATP-driven Mrp1.
“which is mainly mediated by the ATP‐driven Mrp1 (Hirrlinger et al. 2002b; Minich et al. 2006).”
From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Minich et al. 2006
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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Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion
Verkhratsky, A., Matteoli, M., Parpura, V., Mothet, J., & Zorec, R. (2016) · The EMBO Journal · doi:10.15252/embj.201592705 · Cited by 397 · 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
Self-citationA thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death
Ceder, S., Eriksson, S. E., Cheteh, E. H., Dawar, S., Corrales Benitez, M., Bykov, V. J. N., Fujihara, K. M., Grandin, M., Li, X., Ramm, S., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.201910852 · Cited by 41 · see citing works
l-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes
Takeshima, M., Miyazaki, I., Murakami, S., Kita, T., & Asanuma, M. (2016) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.16-15 · Cited by 31 · see citing works
- Authors
- Minich, T., Riemer, J., Schulz, J. B., Wielinga, P., Wijnholds, J., & Dringen, R.
- Affiliations
- University of Tübingen (DE)
- University of Göttingen (DE)
- The Netherlands Cancer Institute (NL)
- Royal Netherlands Academy of Arts and Sciences (NL)
- University of Bremen (DE)
- Corresponding author
- Dringen, Ralf
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2006-03-15
- Volume
- 97
- Issue
- 2
- Pages
- 373-384
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1558564171
- Cited by
- 185
- References
- 1
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 14 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 10 · 2014: 14 · 2013: 20 · 2012: 13
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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 › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- multidrug resistance protein 1, MRP5, glutathione export, glutathione disulfide, astrocytes, MK571, hydrogen peroxide stress, glutathione transport
- MeSH terms
- Animals, Animals, Newborn, Astrocytes, Brain, Cell Survival, Dose-Response Relationship, Drug, Enzyme Inhibitors, Glutathione, Hydrogen Peroxide, Propionates, Quinolines, RNA, Messenger, Time Factors, Blotting, Northern, Minor Histocompatibility Antigens, Mice, Knockout, Glutathione Disulfide, Leukotriene Antagonists, Reverse Transcriptase Polymerase Chain Reaction, Protein Transport, ATP-Binding Cassette, Sub-Family C Proteins, Mice
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