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Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury
- Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury
- Bae S.H.; Sung S.H.; Lee H.E.; Kang H.T.; Lee S.K.; Oh S.Y.; Woo H.A.; Kil I.S.; Rhee S.G.
- Ewha Authors
- 이서구; 배수한; 길인섭; 우현애
- SCOPUS Author ID
- 이서구; 우현애
- Issue Date
- Journal Title
- Antioxidants and Redox Signaling
- Antioxidants and Redox Signaling vol. 17, no. 10, pp. 1351 - 1361
- SCI; SCIE; SCOPUS
- Document Type
- Aims: To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress. Results: Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1-independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole upregulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazoleinduced oxidative damage to the liver was greater in PrxIII -/- mice than in wild-type mice. Such damage was also increased in Srx -/- mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII. Innovation: The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity. Conclusion: The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria. © 2012 Mary Ann Liebert, Inc.
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