title: Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury.
abstract: OBJECTIVE
  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 up-regulated 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. Pyrazole-induced 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.
  
  
  METHODS
  The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea. soohanbae@ewha.ac.kr
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
authors.forename: Su Haeng
authors.initials: SH
authors.lastname: Sung
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Ha Tan
authors.initials: HT
authors.lastname: Kang
authors.forename: Se Kyoung
authors.initials: SK
authors.lastname: Lee
authors.forename: Sue Young
authors.initials: SY
authors.lastname: Oh
authors.forename: Hyun Ae
authors.initials: HA
authors.lastname: Woo
authors.forename: In Sup
authors.initials: IS
authors.lastname: Kil
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D061105:Peroxiredoxin III / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000633:toxicity*
chemical_list: D051267:NF-E2-Related Factor 2; D011720:Pyrazoles; C031280:pyrazole; D061105:Peroxiredoxin III; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse