The role of active oxygen species and lipidperoxidation in the pathogenesis of duodenal ulcersinduced by mepirizole was investigated in rats. Oraladministration of mepirizole (200 mg/kg) resulted in ulcer lesions in the proximal duodenum.Thiobarbituric acid-reactive substances (TBA-reactivesubstances), an indicator of lipid peroxidation, alsosignificantly increased in the duodenal mucosa.Myeloperoxidase (MPO) activity in the duodenal mucosa, a signof polymorphonuclear leukocyte (PMN) accumulation,significantly increased. Combination treatment withpolyethylene glycol-modified Serratia Mn-SOD andcatalase significantly decreased the size of the ulcersand TBA-reactive substances in the duodenal mucosa.Allopurinol, a xanthine oxidase inhibitor, also reducedthe size of duodenal ulcers. Both the size of the ulcers and the increase in TBA-reactivesubstances in the duodenal mucosa were significantlylower in PMN-depleted rats. Mepirizole increased thesurface expression of adhesion molecule CD18 on PMNs in vitro. These results suggest that lipidperoxidation, mediated by active oxygen speciesgenerated from xanthine oxidase and PMNs, plays animportant role in the pathogenesis of duodenal ulcersinduced by mepirizole.