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. (HEPATOLOGY 2011) Chronic ethanol consumption increases the production of a variety of reactive oxygen species (ROS), including superoxide, H2O2, Neratinib cell line lipid peroxides, and peroxynitrite in the liver, an effect that has been implicated

as a major factor in the pathogenesis of alcohol-induced liver disease.1-4 Accumulation of ROS induces the expression of antioxidant enzyme genes through activation of a cis-acting see more element known as the antioxidant-responsive element (ARE). Transcription factors that transmit the oxidative stress signal to the ARE include nuclear factor erythroid 2-related factor 2 (Nrf2) and activator protein-1 (AP-1).5 Exposure of animals to chronic ethanol feeding or overexpression of cytochrome

P450 2E1 (CYP2E1) in hepatocytes thus increases the expression of Mn2+-dependent superoxide dismutase (SOD) and heme oxygenase-1 by activating Nrf2 or AP-1 or both.3, 6, 7 Peroxiredoxins (Prxs) are a family of peroxidases that reduce peroxides and peroxynitrite with the use of reducing equivalents provided by thiol-containing proteins.8 Prxs contain a conserved cysteine residue (designated the peroxidatic cysteine, CP) in the NH2-terminal region that is the primary site of oxidation by H2O2. Mammalian tissues express six distinct Prx gene products (Prx I to VI), which can be divided into three subgroups: 2-Cys, atypical 2-Cys, and 1-Cys.8 Members of the 2-Cys subgroup (Prx I to IV) contain an additional conserved cysteine (designated the resolving cysteine, CR) in the COOH-terminal region, whereas Prx V and VI, members of the atypical 2-Cys and 1-Cys subgroups, respectively, do not 上海皓元医药股份有限公司 contain this second conserved cysteine. Prx isoforms show distinct intracellular distributions, with Prx I and II being localized predominantly in the cytosol,

Prx III being restricted to mitochondria, Prx IV being found mainly in the endoplasmic reticulum (ER), Prx V being detected in the cytosol and mitochondria, and Prx VI being present in the cytosol.8 In the catalytic cycle of 2-Cys Prx enzymes, which exist as homodimers, CP-SH is first converted to cysteine sulfenic acid (CP-SOH) by a peroxide. The unstable sulfenic intermediate then reacts with the CR-SH of the other subunit of the dimer to form a disulfide, which is subsequently reduced by thioredoxin to complete the catalytic cycle.8 As a result of the slow rate of its conversion to a disulfide, the sulfenic intermediate is occasionally oxidized further to cysteine sulfinic acid (CP-SO2H), leading to inactivation of peroxidase activity.9 This hyperoxidation is reversed by the ATP-dependent enzyme sulfiredoxin (Srx).