HYDROXYL RADICAL IS THE MAJOR CAUSATIVE FACTOR IN STRESS-INDUCED GASTRIC-ULCERATION

The role of the metal-catalyzed production of hydroxyl radicals (OH.) on gastric ulceration caused by restraint-cold stress in rat was studi ed. Stress causes a 50% increase in the thiobarbituric acid reactive s pecies (TBARS) as a measure of the lipid peroxidation; nearly 70% incr ease in protein oxidation as measured by its carbonyl content and abou t 40% decrease in the glutathione content of the fundic stomach, sugge sting oxidative damage by stress. Stress also causes a time-dependent increase in the mitochondrial superoxide dismutase activity and a decr ease in the peroxidase activity, both of which correlate well with the increase in the severity of ulceration as measured by the ulcer index . Specific OH. scavengers such as benzoate or dimethylsulfoxide (DMSO) and the free radical trap such as alpha-phenyl N-tert-butyl nitrone ( PBN) significantly inhibit gastric ulceration suggesting the role of O H. in this oxidative damage. Desferrioxamine (DFO), a nontoxic transit ion metal ion chelator, protects the mucosa against stress-ulceration dose dependently. Increased level of TBARS and the inactivation of gas tric peroxidase are also prevented by DFO or by antioxidants such as g lutathione or vitamin E, suggesting the critical role of metal ion and OH. in the oxidative damage. A metal-catalyzed OH. generating system constituted by Cu2+, H2O2 and ascorbate (reducing equivalent of O-2(-) ) causes inactivation of the purified gastric peroxidase in vitro, whi ch can be effectively prevented by DFO. The stress-induced activation of the superoxide dismutase is completely blocked by pretreatment with alpha-amanitin indicating an increased synthesis of the enzyme by inc reased transcription of its m-RNA. Quantitative measurement indicates that stress causes a fivefold increase in the generation of OH., which correlates well with the increase in ulcer index with the progress of stress. The results indicate that the stress-induced gastric ulcerati on is a consequence of the oxidative damage of the gastric mucosa. Thi s is caused by the OH. generated through the metal-catalyzed Haber-Wei ss reaction between O-2(-) and H2O2, the latter being formed by the st imulation of the superoxide dismutase and inactivation of the gastric peroxidase. (C) 1997 Elsevier Science Inc.