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

Abstract

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.