Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury

Soo Han Bae, Su Haeng Sung, Hye Eun Lee, Ha Tan Kang, Se Kyoung Lee, Sue Young Oh, Hyun Ae Woo, In Sup Kil, Sue Goo Rhee

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish
Pages (from-to)1351-1361
Number of pages11
JournalAntioxidants and Redox Signaling
Issue number10
StatePublished - 15 Nov 2012


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