CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons
Abstract
Increasing evidence suggests that brain cytochrome P450 (CYP) can contribute to the in situ metabolism of xenobiotics. In the liver, some xenobiotics can be metabolized by CYPs into more reactive products that can damage hepatocytes and induce cell death. In addition, normal CYP activity may produce reactive oxygen species (ROS) that contribute to cell damage through oxidative mechanisms. CYP2E1 is a CYP isoform that can generate ROS leading to cytotoxicity in multiple tissue types. The aim of this study was to determine whether CYP2E1 induction may lead to significant brain cell impairment. Immunological analysis revealed that exposure of primary cerebellar granule neuronal cultures to the CYP inducer isoniazid, increased CYP2E1 expression. In the presence of buthionine sulfoximine, an agent that reduces glutathione levels, isoniazid treatment also resulted in reactive oxygen species (ROS) production, DNA oxidation and cell death. These effects were attenuated by simultaneous exposure to diallyl sulfide, a CYP2E1 inhibitor, or to a mimetic of superoxide dismutase/catalase, (Euka). These results suggest that in cases of reduced antioxidant levels, the induction of brain CYP2E1 could represent a risk of in situ neuronal damage.
Integrity signals
Registry
Cites
Statistics
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?
The role of CYP2E1 in brain ethanol metabolism and its association with alcohol-mediated oxidative neuronal injury and aging-related AD and PD have been suggested.
“The role of CYP2E1 in brain ethanol metabolism and its association with alcohol-mediated oxidative neuronal injury155–160 and aging-related AD and PD161 have also been suggested.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [160]
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
Tietze, F. (1969) · Analytical Biochemistry · doi:10.1016/0003-2697(69)90064-5 · Cited by 6,077 · see citing works
Rahman, I., Kode, A., & Biswas, S. K. (2006) · Nature Protocols · doi:10.1038/nprot.2006.378 · Cited by 2,262 · see citing works
Ding, X., & Kaminsky, L. S. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140251 · Cited by 819 · see citing works
CYP2E1 and oxidative liver injury by alcohol
Lu, Y., & Cederbaum, A. I. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.11.004 · Cited by 805 · see citing works
Bains, J. S., & Shaw, C. A. (1997) · Brain Research Reviews · doi:10.1016/s0165-0173(97)00045-3 · Cited by 716 · see citing works
Role of CYP2E1 in the Hepatotoxicity of Acetaminophen
Lee, S. S. T., Buters, J., Pineau, T., Fernández‐Salguero, P. M., & Gonzalez, F. J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.20.12063 · Cited by 655 · see citing works
Madan, A., Graham, R., Carroll, K. M., Mudra, D. R., Burton, L. A., Krueger, L. A., Downey, A., Czerwiński, M., Forster, J., Ribadeneira, M. D., et al. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.4.421 · Cited by 338 · see citing works
Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites
Brady, J. F., Ishizaki, H., Fukuto, J. M., Lin, M. C., Fadel, A., Gapac, J. M., & Yang, C. S. (1991) · Chemical Research in Toxicology · doi:10.1021/tx00024a008 · Cited by 262 · see citing works
Cytochrome P450 enzymes in the brain: emerging evidence of biological significance
Ferguson, C. S., & Tyndale, R. F. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2011.08.005 · Cited by 241 · see citing works
Dai, Y., Rashba-Step, J., & Cederbaum, A. I. (1993) · Biochemistry · doi:10.1021/bi00078a017 · Cited by 240 · see citing works
Morgan, E. T., Koop, D. R., & Coon, M. J. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)45325-8 · Cited by 235 · see citing works
Applying Mechanisms of Chemical Toxicity to Predict Drug Safety
Guengerich, F. P., & MacDonald, J. S. (2007) · Chemical Research in Toxicology · doi:10.1021/tx600260a · Cited by 230 · see citing works
Ethanol Increases Cytochrome P4502E1 and Induces Oxidative Stress in Astrocytes
Montoliu, C., Sancho‐Tello, M., Azorin, I., Burgal, M., Vallés, S., Renau‐Piqueras, J., & Guerri, C. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65062561.x · Cited by 218 · see citing works
Gonzalez, F. J. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.012492 · Cited by 214 · see citing works
CYP2E1-dependent toxicity and oxidative stress in HepG2 cells,
Cederbaum, A. I. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00743-2 · Cited by 210 · see citing works
Salen-Manganese Complexes Are Superoxide Dismutase-Mimics
Baudry, M., Etienne, S., Bruce‐Keller, A. J., Palucki, M., Jacobsen, E., & Malfroy, B. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.1509 · Cited by 207 · see citing works
Wüllner, U., Seyfried, J., Groscurth, P., Beinroth, S., Winter, S., Gleichmann, M., Heneka, M. T., Löschmann, P.-A., Schulz, J. B., Weller, M., et al. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01228-7 · Cited by 183 · see citing works
DNA repair, mitochondria, and neurodegeneration
Weissman, L., de Souza-Pinto, N. C., Stevnsner, T., & Bohr, V. A. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.08.061 · Cited by 171 · see citing works
Cytotoxicity and Apoptosis Produced by Cytochrome P450 2E1 in Hep G2 Cells
Chen, Q., & Cederbaum, A. I. (1998) · Molecular Pharmacology · doi:10.1124/mol.53.4.638 · Cited by 166 · see citing works
Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans
Zand, R., Nelson, S. D., Slattery, J. T., et al. (1993) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1993.125 · Cited by 156 · see citing works
Mammalian cytochromes P450—Importance of tissue specificity
Seliškar, M., & Rozman, D. (2006) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2006.09.016 · Cited by 154 · see citing works
Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics
Howard, L. A., Miksys, S. L., Hoffmann, E. B., Mash, D. C., & Tyndale, R. F. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705146 · Cited by 142 · see citing works
Upadhya, S. C., Tirumalai, P. S., Boyd, M. R., Mori, T., & Ravindranath, V. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1999.1477 · Cited by 132 · see citing works
Dutheil, F., Beaune, P. H., & Loriot, M. (2007) · Biochimie · doi:10.1016/j.biochi.2007.10.007 · Cited by 121 · see citing works
Oxidation Kinetics of Ethanol by Human Cytochrome P450 2E1
Bell, L. C., & Guengerich, F. P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.47.29643 · Cited by 104 · see citing works
Induction of brain cytochrome P-450IIE1 by chronic ethanol treatmen
Anandatheerthavarada, H. K., Shankar, S. K., Bhamre, S., Boyd, M. R., Song, B.-J., & Ravindranath, V. (1993) · Brain Research · doi:10.1016/0006-8993(93)91721-4 · Cited by 90 · see citing works
Removal of Glutathione Produces Apoptosis and Necrosis in HepG2 Cells Overexpressing CYP2E1
Wu, D., & Cederbaum, A. I. (2001) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2001.tb02259.x · Cited by 80 · see citing works
Zhong, Y., Dong, G., Luo, H., Cao, J., Wang, C., Wu, J., Feng, Y.-Q., & Yue, J. (2012) · Toxicology · doi:10.1016/j.tox.2012.08.009 · Cited by 77 · see citing works
On the occurrence of cytochrome P-450 and aryl hydrocarbon hydroxylase activity in rat brain.
Cohn, J. A., Alvares, A. P., & Kappas, A. (1977) · The Journal of Experimental Medicine · doi:10.1084/jem.145.6.1607 · Cited by 70 · see citing works
Mann, A., & Tyndale, R. F. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07142.x · Cited by 67 · see citing works
CYP2E1 and risk of chemically mediated cancers
Trafalis, D. T., Panteli, E. S., Grivas, A., et al. (2010) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250903540238 · Cited by 66 · see citing works
Characterization of microsomal aryl hydrocarbon hydroxylase of rat brain.
Das, M., Seth, P. K., & Mukhtar, H. (1981) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)32391-8 · Cited by 62 · see citing works
Morán, J., & Patel, A. J. (1989) · Developmental Brain Research · doi:10.1016/0165-3806(89)90146-6 · Cited by 61 · see citing works
Self-citationTranslational activation of ethanol-inducible cytochrome P450 (CYP2E1) by isoniazid
Park, K. S., Sohn, D. H., Veech, R. L., & Song, B. J. (1993) · European Journal of Pharmacology Environmental Toxicology and Pharmacology · doi:10.1016/0926-6917(93)90019-m · Cited by 61 · see citing works
Bhagwat, S. V., Boyd, M. R., & Ravindranath, V. (1995) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1995.1344 · Cited by 61 · see citing works
Rat Brain CYP2B-Enzymatic Activation of Chlorpyrifos to the Oxon Mediates Cholinergic Neurotoxicity
Khokhar, J. Y., & Tyndale, R. F. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs029 · Cited by 60 · see citing works
Sánchez-Martín, F. J., Fernández‐Salguero, P. M., & Merino, J. M. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07291.x · Cited by 56 · see citing works
Khokhar, J. Y., & Tyndale, R. F. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.202 · Cited by 54 · see citing works
INDUCTION AND RECOVERY TIME COURSE OF RAT BRAIN CYP2E1 AFTER NICOTINE TREATMENT
Joshi, M., & Tyndale, R. F. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.008029 · Cited by 52 · see citing works
Glutathione and the Regulation of Cell Death
Hall, A. G. (1999) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-4811-9_21 · Cited by 47 · see citing works
Expression of constitutive and inducible cytochrome P450 2E1 in rat brain
Yadav, S., Dhawan, A., Singh, R. L., Seth, P. K., & Parmar, D. (2006) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-005-9109-z · Cited by 45 · see citing works
First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo
Zhou, K., Khokhar, J. Y., Zhao, B., et al. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.04.014 · Cited by 40 · see citing works
Isoniazid-induced hepatotoxicity in rat hepatocytes of gel entrapment culture
Shen, C., Zhang, H., Zhang, G., et al. (2006) · Toxicology Letters · doi:10.1016/j.toxlet.2006.08.010 · Cited by 34 · see citing works
Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats
Yue, J., Dong, G., He, C., et al. (2009) · Toxicology · doi:10.1016/j.tox.2009.08.006 · Cited by 33 · see citing works
Miller, K. J., Anderholm, D. C., & Ames, M. M. (1986) · Biochemical Pharmacology · doi:10.1016/0006-2952(86)90332-1 · Cited by 24 · see citing works
Upadhya, S. C., Boyd, M. R., & Ravindranath, V. (2001) · Neurotoxicity Research · doi:10.1007/bf03033198 · Cited by 9 · see citing works
Gastro-intestinal absorption of isoniazid and rifampicin in patients with intestinal tuberculosis
Gurumurthy, P., Ramachandran, R., Balasubramanian, R., et al. (1990) · NIRT Institutional Scholarship Repository (National Institute of Research in Tuberculosis) · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Rungratanawanich, W., Qu, Y., Wang, X., Essa, M. M., & Song, B.-J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00561-7 · Cited by 411 · see citing works
- Authors
- Valencia-Olvera, A. C., Morán, J., Camacho-Carranza, R., Prospéro-García, O., & Espinosa-Aguirre, J. J.
- Affiliations
- Universidad Nacional Autónoma de México (MX)
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (MX)
- Corresponding author
- Espinosa-Aguirre, Jesús Javier
- Venue
- Toxicology in Vitro
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 28
- Issue
- 7
- Pages
- 1206-1214
- ISSN
- 0887-2333 (ISSN-L)
- OpenAlex
- W2008455078
- Cited by
- 36
- References
- 48
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 7 · 2017: 4 · 2016: 4 · 2015: 3
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology in Vitro (publishedVersion)
- PubMed (publishedVersion)
- Funders
- DGAPA-UNAM (IN214908)
- CONACYT
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- CYP2E1 induction, cerebellar granule cells, oxidative stress, cytotoxicity, glutathione depletion, isoniazid, reactive oxygen species, DNA oxidation, buthionine sulfoximine, diallyl sulfide, neuronal injury
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Cerebellum, DNA, Glutathione, Isoniazid, Neurons, Oxidation-Reduction, Reactive Oxygen Species, Oxidative Stress, Cytochrome P-450 CYP2E1, Rats, Cytochrome P-450 CYP2E1 Inducers
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