Critical role of an endogenous gastric peroxidase in controlling oxidative damage in H. pylori-mediated and nonmediated gastric ulcer

The objective of the present study is to delineate the mechanism of oxidative damage in human gastric ulcerated mucosa despite the presence of some antioxidant enzymes. We report for the first time the critical role of an endogenous peroxidase, a major H2O2 metabolizing enzyme, in controlling oxidative damage in gastric mucosa. Human gastric mucosa contains a highly active peroxidase in addition to the myeloperoxidase contributed by neutrophil. In both non-Helicobacter pylori (H. pylori)- and H. pylori-mediated gastric ulcer, when myeloperoxidase level increases due to neutrophil accumulation, gastric peroxidase (GPO) level decreases significantly. Moreover, gastric ulcer is associated with oxidative damage of the mucosa as evidenced by significant increase in lipid peroxidation, protein oxidation, and thiol depletion indicating accumulation of reactive oxygen metabolites (ROM). Mucosal total superoxide dismutase (Mn and Cu-Zn SOD) level also decreases significantly leading to increased accumulation of O2•−. To investigate the plausible ROM-mediated inactivation of the GPO during ulceration, the enzyme was partially purified from the mucosa. When exposed to an in vitro ROM generating system, using Cu2+, ascorbate, and H2O2, the enzyme gets inactivated, which is dependent on Cu2+, ascorbate, or H2O2. Insensitivity to SOD excludes inactivation by O2•−. However, complete protection by catalase indicates that H2O2 is essential for inactivation. Sensitivity to EDTA and hydroxyl radical (√OH) scavengers indicates that GPO is inactivated most probably by √OH generated from H2O2. We propose that GPO is inactivated in vivo by ROM generated by activated neutrophil. This leads to further accumulation of endogenous H2O2 to cause more oxidative damage to aggravate the ulcer.