Ethacrynic acid and its glutathione conjugate as inhibitors of glutathione S-transferases
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1. The diuretic drug ethacrynic acid (EA) is a potent reversible inhibitor of rat and human glutathione S-transferases (GST), with I50-values (microM) of 4.6-6.0, 0.3-1.9 and 3.3-4.8 for alpha, mu and pi-class, respectively. 2. The reversible inhibition by the glutathione conjugate of EA is even stronger for alpha and mu-class, with I50-values (microM) of 0.8-2.8 and < 0.1-1.2, respectively, while the I50 for the pi-class is 11. 3. Inhibition of rat and human pi-class GST also occurs by covalent binding of ethacrynic acid. 14C-ethacrynic acid, 0.8 nmol EA per nmol pi-class GST could be incorporated, resulting in 65-93% inhibition of the catalytic activity. 4. Owing to the chemical nature of the covalent binding (Michael addition), this reaction should be reversible. Indeed, full restoration of the catalytic activity of GST P1-1 inactivated by covalently-bound EA was reached in about 125 h by incubation with an excess of glutathione. 5. EA has been used to inhibit GST in biological systems. The reversible covalent binding may very well play a role in the observed inhibition of GST by EA in vivo.
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Ethacrynic acid is a loop diuretic that inhibits GSTM-subfamily proteins, in part by acting as an alternative substrate for glutathione conjugation.
“Ethacrynic acid is a loop diuretic that inhibits GSTM-subfamily proteins, in part by acting as an alternative substrate for glutathione conjugation (47, 48).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [47]
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- Authors
- Ploemen, J. H. T. M., Ommen, B. V., Bogaards, J. J. P., & Van Bladeren, P. J.
- ORCID
- Ommen, B. Van
- Venue
- Xenobiotica
- Publisher
- Informa UK Limited
- Published
- 1993-01
- Volume
- 23
- Issue
- 8
- Pages
- 913-923
- ISSN
- 0049-8254 (ISSN-L)
- 1366-5928
- OpenAlex
- W2139026524
- Cited by
- 94
- References
- 52
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 12 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 7 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 3
- FWCI
- 0.12
- Type
- journal article
- Language
- en
- Open access
- green
- research.wur.nl
- Locations
- Xenobiotica (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- TNO Repository (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- ethacrynic acid, glutathione S-transferase, GST inhibitors, glutathione conjugates, reversible inhibition, covalent binding, Michael addition, diuretics, enzyme inactivation, glutathione
- MeSH terms
- Animals, Ethacrynic Acid, Glutathione, Glutathione Transferase, Humans, Molecular Structure
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