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Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol‐induced oxidative injury in mouse liver
Author(s) -
Bae Soo Han,
Sung Su Haeng,
Cho Eun Jung,
Lee Se Kyoung,
Lee Hye Eun,
Woo Hyun Ae,
Yu DaeYeul,
Kil In Sup,
Rhee Sue Goo
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24104
Subject(s) - cyp2e1 , peroxiredoxin , reactive oxygen species , chemistry , biochemistry , ethanol , endoplasmic reticulum , liver injury , oxidative stress , peroxidase , microbiology and biotechnology , biology , pharmacology , enzyme , cytochrome p450
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. (H EPATOLOGY 2011)