Nrf2 and Antioxidant Defense Against CYP2E1 Toxicity
Abstract
The transcription factor Nrf2 regulates the expression of important cytoprotective enzymes. Induction of cytochrome P450 2E1(CYP2E1) is one of the central pathways by which ethanol generates oxidative stress. CYP2E1 can be induced by ethanol and several low molecular weight chemicals such as pyrazole. The chapter discusses biochemical and toxicological effects of CYP2E1 and the effects of Nrf2 in modulating these actions of CYP2E1.Besides ethanol, CYP2E1 metabolizes and activates many other important toxicological compounds. One approach to try to understand basic effects and actions of CYP2E1 was to establish HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells which express CYP2E1 (E47 cells) but not control C34HepG2 cells which do not express CYP2E1.Toxicity was associated with enhanced oxidant stress and could be prevented by antioxidants and potentiated if glutathione (GSH) was removed. The E47 cells had higher GSH levels and a Twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 (HO-1) than control HepG2 cells due to activation of their respective genes. These activations were prevented by antioxidants, suggesting that reactive oxygen species (ROS) generated by CYP2E1 were responsible for the up-regulation of these antioxidant genes. This upregulation of antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. In…
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Many GST protein family members act as tumor promoters by influencing reactive oxygen species (ROS).
“Many GST protein family members act as tumor promoters by influencing reactive oxygen species (ROS) (51–56).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [56]
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Seitz, H. K., Bataller, R., Cortez-Pinto, H., Gao, B., Gual, A., Lackner, C., Mathurin, P., Mueller, S., Szabo, G., & Tsukamoto, H. (2018) · Nature Reviews Disease Primers · doi:10.1038/s41572-018-0014-7 · Cited by 1,271 · see citing works
The origin of hepatocellular carcinoma depends on metabolic zonation
Guo, J., Liang, R., Chung, A., Li, Z., Li, B., Chen, E., Li, L., Wang, J., Hsieh, M.-H., Fang, I. X., et al. (2026) · Science · doi:10.1126/science.adv7129 · Cited by 24 · see citing works
Nrf2 signaling pathway: focus on oxidative stress in osteoporosis
Gu, H.-Y., Liu, N., Lin, F.-X., & Yin, J. (2025) · Osteoporosis International · doi:10.1007/s00198-025-07592-0 · Cited by 10 · see citing works
- Authors
- Cederbaum, A. I.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Cederbaum, Arthur I.
- Venue
- Subcellular Biochemistry
- Publisher
- Springer Netherlands
- Published
- 2013
- Volume
- 67
- Pages
- 105-130
- ISSN
- 0306-0225 (ISSN-L)
- OpenAlex
- W1486627395
- Cited by
- 47
- References
- 2
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 4 · 2015: 1 · 2014: 3
- FWCI
- 1.75
- Type
- book chapter
- Language
- en
- Open access
- closed
- Licence
- Locations
- Sub-cellular biochemistry/Subcellular biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- Nrf2, CYP2E1, oxidative stress, antioxidant defense, ethanol toxicity, pyrazole derivatives, glutathione, reactive oxygen species, heme oxygenase-1, glutathione S-transferase, catalase, lipid peroxidation, mitochondrial membrane potential, HepG2 cells, chronic alcohol feeding, siRNA knockdown
- MeSH terms
- Ethanol, Animals, Antioxidants, Central Nervous System Depressants, Humans, Signal Transduction, Oxidative Stress, Cytochrome P-450 CYP2E1, NF-E2-Related Factor 2, Mice, Rats, Cytochrome P-450 CYP2E1 Inhibitors
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