Cited by 36Pharmacogenetics and Drug MetabolismDrug-Induced Hepatotoxicity and ProtectionRedox biology and oxidative stress

CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons

Valencia-Olvera, Ana Carolina, Morán, Julio, Camacho-Carranza, Rafael, Prospéro-García, Oscar, Espinosa-Aguirre, Jesús Javier·2014·Toxicology in Vitro

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.

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Crossref · 10.1016/j.tiv.2014.05.014

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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

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