Concerted Action of Sulfiredoxin and Peroxiredoxin I Protects Against Alcohol-Induced Oxidative Injury in Mouse Liver σ
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UNLABELLED: Peroxiredoxins (Prxs) are peroxidases that catalyze the reduction of reactive oxygen species (ROS). The active site cysteine residue of members of the 2-Cys Prx subgroup (Prx I to IV) of Prxs is hyperoxidized to cysteine sulfinic acid (Cys-SO(2) ) during catalysis with concomitant loss of peroxidase activity. Reactivation of the hyperoxidized Prx is catalyzed by sulfiredoxin (Srx). Ethanol consumption induces the accumulation of cytochrome P450 2E1 (CYP2E1), a major contributor to ethanol-induced ROS production in the liver. We now show that chronic ethanol feeding markedly increased the expression of Srx in the liver of mice in a largely Nrf2-dependent manner. Among Prx I to IV, only Prx I was found to be hyperoxidized in the liver of ethanol-fed wildtype mice, and the level of Prx I-SO(2) increased to ≈30% to 50% of total Prx I in the liver of ethanol-fed Srx(-/-) mice. This result suggests that Prx I is the most active 2-Cys Prx in elimination of ROS from the liver of ethanol-fed mice and that, despite the up-regulation of Srx expression by ethanol, the capacity of Srx is not sufficient to counteract the hyperoxidation of Prx I that occurs during ROS reduction. A protease protection assay revealed that a large fraction of Prx I is located together with CYP2E1 at the cytosolic side of the endoplasmic reticulum membrane. The selective role of Prx I in ROS removal is thus likely attributable to the proximity of Prx I and CYP2E1. CONCLUSION: The pivotal functions of Srx and Prx I in protection of the liver in ethanol-fed mice was evident from the severe oxidative damage observed in mice lacking either Srx or Prx I.
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Oxidative modification of the active site Cys residue of peroxiredoxin 1 (Prx1) and inactivation was observed in alcohol-exposed mice.
“Furthermore, oxidative modification of the active site Cys residue of peroxiredoxin 1 (Prx1) and inactivation was observed in alcohol-exposed mice [47].”
Based on conserved redox-sensitive Cys residues among multiple isoforms, many Prx enzymes could be oxidatively-modified and inactivated, contributing to elevated oxidative stress.
“Based on the conserved redox-sensitive Cys residues among the multiple isoforms [47], [48], [49], many Prx enzymes could be also oxidatively-modified and inactivated, contributing to elevated levels of oxidative stress.”
Since Prx1 is localized on the cytosolic side of the endoplasmic reticulum and interacts with CYP2E1, its oxidative inactivation likely contributes to increased ROS production and fatty liver following alcohol exposure.
“Since Prx1 was determined to be localized on the cytosolic side of the endoplasmic reticulum (ER) and interacts with CYP2E1 [47], it is likely that this oxidative inactivation of Prx1 contributes to increased ROS production and fatty liver following alcohol exposure.”
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Role of nrf2 in oxidative stress and toxicity
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“In addition, we highlight potential roles of CYP2E1 in promoting various PTMs. Post-translational modifications of mitochondrial proteins”
BackgroundInfluential
- Authors
- Bae, S. H., Sung, S. H., Cho, E. J., Lee, S. K., Lee, H. E., Woo, H. A., Yu, D.-Y., Kil, I. S., & Rhee, S. G.
- Affiliations
- Ewha Womans University (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Corresponding author
- Bae, Soo Han
- Rhee, Sue Goo
- Venue
- Hepatology
- Published
- 2011-03
- Volume
- 53
- Issue
- 3
- Pages
- 945-953
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2003627173
- Cited by
- 93
- References
- 39
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 10 · 2019: 5 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 9 · 2012: 10
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- KRIBB Repository (submittedVersion)
- Funders
- National Honor Scientist (2006-05106)
- Bio R&D program grant (M10642040001-07N4204-00110)
- BK21 program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- sulfiredoxin, peroxiredoxin 1, 2-Cys peroxiredoxin, ethanol-induced oxidative stress, liver, reactive oxygen species, CYP2E1, Nrf2, cysteine sulfinic acid, hyperoxidation, endoplasmic reticulum
- MeSH terms
- Ethanol, Animals, Male, Oxidation-Reduction, Reactive Oxygen Species, Cytochrome P-450 CYP2E1, Oxidoreductases Acting on Sulfur Group Donors, Mice, Peroxiredoxins, Chemical and Drug Induced Liver Injury, Peroxiredoxin III
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