title: Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol-induced oxidative injury in mouse liver.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Life Science, 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: Eun Jung
authors.initials: EJ
authors.lastname: Cho
authors.forename: Se Kyoung
authors.initials: SK
authors.lastname: Lee
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Hyun Ae
authors.initials: HA
authors.lastname: Woo
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
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 / Q000378:metabolism / Q000517:prevention & control*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000172:deficiency / Q000378:metabolism*; D061105:Peroxiredoxin III; D054464:Peroxiredoxins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C516116:Prdx3 protein, mouse; D017382:Reactive Oxygen Species; D000431:Ethanol; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; D019392:Cytochrome P-450 CYP2E1; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse