The DOI matches its Crossref record.
Alkylation-Induced Oxidative Cell Injury of Renal Proximal Tubular Cells: Involvement of Glutathione Redox-Cycle Inhibition
Abstract
The nephrotoxicant S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is an alkylating agent that causes oxidative stress and subsequently death of renal proximal tubular cells (PTC). In this paper the role of inhibition of the glutathione redox cycle (GSH-reductase (GRd) and -peroxidase (GPx) in the development of DCVC-induced oxidative cell injury is described. DCVC inhibited both GRd and GPx activity in PTC. Inhibition occurred already after 10 min incubation while at that time point lipid peroxidation and cell death had not started yet; the antioxidant N,N-diphenyl-p-phenylenediamine did not prevent inhibition of GRd and Gpx- inhibition of L-cysteine S-conjugate beta-lyase-mediated formation of reactive metabolites using aminooxyacetic acid, which prevented covalent binding to cellular macromolecules, was associated with prevention of the DCVC-induced inhibition of both enzymes. Covalent binding of reactive metabolites of [35S]DCVC to several cellular proteins was found, including proteins which had molecular weights identical to subunits of GPx and GRd. An inhibitor of GRd, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), potentiated the oxidative cell injury caused by DCVC, whereas BCNU itself did not use oxidative stress and cell death. The thiol-reducing compound dithiothreitol prevented the oxidative cell injury whereas oxidation of cellular thiols with diamide potentiated the DCVC-induced oxidative stress and cell death. Moreover, incubation with (R,S)-3-hydroxy-4-pentenoic acid (HPA), which depletes mitochondrial GSH, potentiated the DCVC-induced oxidative cell injury. Neither diamide nor HPA affected the covalent binding and inhibition of the GSH-redox cycle. Together, the data suggest that the inhibition of GRd and GPx, presumably caused by binding of reactive metabolites of DCVC, impairs the cellular antioxidant system, which seems causally related to DCVC-induced oxidative cell injury.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Interestingly, the function of GR can be oxidatively inactivated at a Cys residue in the active site (372, 428).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [428]
In the citing paper
“In studies of renal nephrotoxicity, oxidative inactivation of GR and GPx by alkylating agents was found to contribute to oxidative stress, characterized by increased lipid peroxidation and cell death in renal proximal tubules that involve mitochondrial disruption and the production of excess oxidants by mitochondria (428).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [428]
Citations
Cited by
Redox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588
“In studies of renal nephrotoxicity, oxidative inactivation of GR and GPx by alkylating agents was found to contribute to oxidative stress, characterized by increased lipid peroxidation and cell death in renal proximal tubules that involve mitochondrial disruption and the production of excess oxidants by mitochondria (…”
BackgroundLiu, H., Bowes, R. C., van de Water, B., Sillence, C., Nagelkerke, J. F., & Stevens, J. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.35.21751 · Cited by 373
Self-citationProtective Effect of Quercetin against Gentamicin-Induced Nephrotoxicity in Rats
Abdel-Raheem, I. T., Abdel-Ghany, A. A., & Mohamed, G. A. (2009) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.32.61 · Cited by 198
Tirmenstein, M. A., Nicholls-Grzemski, F. A., Zhang, G., et al. (2000) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(00)00180-0 · Cited by 81
Green tea ameliorates renal oxidative damage induced by gentamicin in rats.
Abdel-Raheem, I. T., El-Sherbiny, G. A., & Taye, A. (2010) · PubMed · Cited by 68
Sakurai, T., Qu, W., Sakurai, M. H., et al. (2002) · Chemical Research in Toxicology · doi:10.1021/tx0101604 · Cited by 58
Leandro, L. F., Munari, C. C., Sato, V. L. F. L., et al. (2013) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2013.03.006 · Cited by 52
Munari, C. C., de Oliveira, P. F., Lima, I. M. D. S., et al. (2012) · Food and Chemical Toxicology · doi:10.1016/j.fct.2012.07.028 · Cited by 44
“There are reports of alkylating agents that rapidly deplete glutathione-S-transferase in mammalian cells, thereby generating oxidative stress (Liu et al., 1996; Van der Walters et al., 1996).”
BackgroundMunari, C. C., Alves, J. M., Bastos, J. K., et al. (2009) · Journal of Applied Toxicology · doi:10.1002/jat.1467 · Cited by 43
Kumar, A., Shalmanova, L., Hammad, A., et al. (2016) · Transplant Immunology · doi:10.1016/j.trim.2016.02.003 · Cited by 37
Rosa, R. M., Moura, D. J., Silva, A. C. R. E., Saffi, J., & Henriques, J. A. P. (2007) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2007.04.005 · Cited by 36
Munari, C. C., de Oliveira, P. F., Leandro, L. F., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111999 · Cited by 30
“There are reports of alkylating agents that rapidly replete gluthatione-Stransferase (GSH) in cells, thereby generating oxidative stress [29].”
BackgroundDuTeaux, S. B., Hengel, M. J., DeGroot, D. E., et al. (2003) · Biology of Reproduction · doi:10.1095/biolreprod.102.014845 · Cited by 29
“The DCVC can be bioactivated by cysteine-conjugate b-lyase (b-lyase), resulting in the formation of a reactive thiol or chlorothioketene [14, 15].”
BackgroundInfluentialRole of reactive metabolites in the circulation in extrahepatic toxicity
Irving, R. M., & Elfarra, A. A. (2012) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2012.695347 · Cited by 29
“GRd activity was reduced in rat renal PT cells treated with DCVC [89] and MDH activity was reduced in rat liver mitochondria in the presence of DCVC [90].”
BackgroundResende, F. A., Tomazella, I. M., Barbosa, L. C., Ponce, M., Furtado, R. A., Pereira, A. C., Bastos, J. K., Silva, M. L. A. E., & Tavares, D. C. (2010) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2010.04.023 · Cited by 27
Acésio, N. O., Carrijo, G. S., Batista, T. H., Damasceno, J. L., Corrêa, M. B., Tozatti, M. G., Cunha, W. R., & Tavares, D. C. (2017) · Journal of Toxicology and Environmental Health · doi:10.1080/15287394.2017.1377653 · Cited by 29
Antigenotoxicity of artepillin C in vivo evaluated by the micronucleus and comet assays
Neto, M. D. A. B. M., Lima, I. M. D. S., Furtado, R. A., et al. (2011) · Journal of Applied Toxicology · doi:10.1002/jat.1614 · Cited by 21
“S‐transferase in mammalian cells, thereby generating oxidative stress (Liu et al., 1996; Van Der Walter et al., 1996).”
BackgroundAndrade, A. F., Alves, J. M., Corrêa, M. B., et al. (2016) · Pharmaceutical Biology · doi:10.1080/13880209.2016.1175022 · Cited by 17
“Alkylating agents have been reported to rapidly reduce glutathione-S-transferases (GSH) in mammalian cells, causing oxidative stress (Liu et al. 1996; Van der Walter et al. 1996).”
BackgroundOliveira, P. F., Neto, M. A. B. M., Leandro, L. F., et al. (2011) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2011.00680.x · Cited by 16
Varatharajan, R., Jun, L. H., Kai, T., et al. (2017) · Journal of Young Pharmacists · doi:10.5530/jyp.2017.9.6 · Cited by 15
Mally, A., & Jarzina, S. (2022) · Frontiers in Toxicology · doi:10.3389/ftox.2022.863643 · Cited by 15
Elkin, E. R., Bridges, D., Harris, S. M., & Loch-Caruso, R. K. (2020) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.9b00356 · Cited by 13
Nephroprotective potential of Graptophyllum pictum against renal injury induced by gentamicin.
Srinivasan, K. K., Mathew, J. E., D'Silva, K. J. A., et al. (2015) · PubMed · Cited by 13
Machado, N. M., Ribeiro, A. B., Nicolella, H. D., et al. (2019) · Journal of Toxicology and Environmental Health · doi:10.1080/15287394.2019.1613274 · Cited by 11
“Alkylating agents were also noted to produce rapid depletion of glutathione S-transferase in mammalian cells, generating oxidative stress (van de Water, Zoeteweij, and Nagelkerke 1996).”
BackgroundOGASAWARA, M., Nomura, K., Shibata, N., Ujihara, M., Kobayashi, M., & Demura, H. (1999) · Endocrine Journal · doi:10.1507/endocrj.46.99 · Cited by 8
“Therefore, the nephrotoxic effect of DCVC is caused by impairing the GSH redox cycle [15].”
BackgroundTrindade, C., Juchem, A. L. M., de Albuquerque, N. R. M., et al. (2015) · Mutagenesis · doi:10.1093/mutage/gev037 · Cited by 7
Chaabane, F., Mokdad-Bzéouich, I., Sassi, A., et al. (2015) · Drug and Chemical Toxicology · doi:10.3109/01480545.2015.1107730 · Cited by 5
“Alkylating agents were reported to rapidly deplete glutathione-S-transferase in mammalian cells, thereby generating oxidative stress (Liu et al., 1996; Van der Walters et al., 1996).”
BackgroundIrving, R. M., Brownfield, M. S., & Elfarra, A. A. (2011) · Chemical Research in Toxicology · doi:10.1021/tx200263n · Cited by 4
Slameňová, D., Kozics, K., Melušová, M., & Horváthová, E. (2015) · Neoplasma · doi:10.4149/neo_2015_086 · Cited by 3
“[43] VAN DE WATER B, ZOETEWEIJ JP, NAGELKERKE JF”
BackgroundZwart, L. D. (1998) · Biomarkers · doi:10.1080/135475098231156 · Cited by 3
van Kessel, H. W., Kunnen, S. J., Callegaro, G., & van de Water, B. (2025) · Toxicological Sciences · doi:10.1093/toxsci/kfaf159 · Cited by 2
“3DII); DCVC is known to induce an Nrf2-mediated antioxidant response in renal proximal tubular epithelial cells (Van De Water et al. 1996).”
Self-citationBarbosa, B. F. F. (2014) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.60.2014.tde-03112014-152357 · Cited by 2
Use of video microscopy to study the mechanisms of cytotoxicity in vitro in individual living cells
Nagelkerke, J. F., & de Bont, H. J. G. M. (1997) · Toxicology in Vitro · doi:10.1016/s0887-2333(97)00046-5 · Cited by 1
Self-citationNagelkerke, J. F., & de Bont, H. J. G. M. (2002) · Chromatographia · doi:10.1007/bf02493348
Self-citation
Metadata
- Authors
- van de Water, B., Zoeteweij, J. P., & Nagelkerke, J. F.
- Affiliations
- Leiden University (NL)
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 1996-03
- Volume
- 327
- Issue
- 1
- Pages
- 71-80
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W2058784251
- Cited by
- 35
- References
- 0
- Citations by year
- 2025: 1 · 2022: 1 · 2020: 1 · 2019: 2 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- S-(1,2-dichlorovinyl)-L-cysteine, alkylating agents, nephrotoxicity, renal proximal tubular cells, oxidative stress, glutathione reductase, glutathione peroxidase, glutathione redox cycle, reactive metabolites, covalent binding, aminooxyacetic acid, BCNU, dithiothreitol, diamide, oxidative cell injury, cell death
- MeSH terms
- Alkylation, Animals, Carmustine, Cysteine, Glutathione, Glutathione Peroxidase, Glutathione Reductase, Hydrogen Peroxide, Kidney Tubules, Proximal, Kinetics, Male, Oxidation-Reduction, Pentanoic Acids, Sulfur Radioisotopes, Cell Death, Rats, Wistar, Glutathione Disulfide, Rats, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
