title: The redox state of the glutathione/glutathione disulfide couple mediates intracellular arginase activation in HCT-116 colon cancer cells.
abstract: BACKGROUND
  Emerging studies have implicated arginase hyperactivity in the dysregulation of nitric oxide synthesis, which can lead to the development of vascular disease and the promotion of tumor cell growth. Recently, we showed that cysteine, in the presence of molecular iron, promotes arginase activity by driving the Fenton reaction. However, the exact mechanism of arginase activation in the cell induced by oxidative stress is unknown.
  
  
  OBJECTIVE
  The aim of the present study is to examine whether intracellular arginase is regulated by the cellular redox status of glutathione.
  
  
  METHODS
  To test this hypothesis, the glutathione/glutathione disulfide redox couple was altered in colon cancer cells with the thiol-specific oxidant, diamide, or the glutathione inhibitor, buthionine-(S,R)-sulfoximine, and the activity of the arginase in the cells was assessed.
  
  
  RESULTS
  Treatment of cells with diamide, a thiol-specific oxidant, resulted in a dose-dependent decrease in the glutathione/glutathione disulfide ratio that was associated with the loss of glutathione and a coincident increase in arginase activity and arginase-1 levels in drug-treated cells compared with untreated cells. These results show that oxidation-induced redox changes of glutathione are of sufficient magnitude to control the activity of arginase in the cells. Thus, the physiologic modulation of the glutathione/glutathione disulfide ratio could prove to be a fundamental parameter for the control of arginase activity in pathological conditions of increased oxidative stress.
  
  
  CONCLUSIONS
  This is the first evidence supporting the ex vivo regulation of arginase activity through the redox modulation of intracellular glutathione. The potential adaptive and pathological consequences of glutathione redox regulation of arginase activity are discussed.
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. eiyamu99@yahoo.com
authors.forename: Efemwonkiekie W
authors.initials: EW
authors.lastname: Iyamu
mesh_terms: D001119:Arginase / Q000378:metabolism*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology*; D003958:Diamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D003958:Diamide; D019328:Buthionine Sulfoximine; D001119:Arginase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide