ROLE OF REBAMIPIDE ON INDUCTION OF HEAT-SHOCK PROTEINS AND PROTECTIONAGAINST REACTIVE OXYGEN METABOLITE-MEDIATED CELL-DAMAGE IN CULTURED GASTRIC-MUCOSAL CELLS

Reactive oxygen metabolites (ROM) have been reported to be important i n the pathogenesis of ischemia/reperfusion-, ethanol-, nonsteroidal an tiinflammatory drug-, or Helicobacter pylori-induced gastric mucosal i njury. Rebamipide, a novel antiulcer agent, has been reported either t o prevent various acute experimental gastric mucosal lesions or to acc elerate the healing of chronic gastric ulcers. The underlying mechanis m by which rebamipide exerts its cytoprotective effect in the damaged stomach is not fully determined. We investigated the role of rebamipid e in protecting against ROM-mediated cell damage in gastric mucosal ce lls and in inducing cytoprotective proteins. Cells were exposed to ROM enzymatically generated by hypoxanthine-xanthine oxidase. Cytotoxicit y was quantified by measuring specific Cr-51 release from prelabeled c ells. ROM caused dose-dependent increase in cytotoxicity and amount of thiobarbituric acid-reactive substances (TBA-RS). ROM-induced cytotox icity and TBA-RS were dose-dependently decreased by the addition of re bamipide and/or catalase, but not by superoxide dismutase alone. The e ffects of rebamipide on electric spin resonance signal were investigat ed. We found that the DMPO spin adduct ESR signal of hydroxyl radicals (DMPO-OH) was significantly attenuated by rebamipide. Western blot an alysis showed that induction of heat-shock protein (HSP70) was signifi cantly increased following rebamipide administration in a dose-depende nt manner. Based on these results, it is concluded that rebamipide exe rted a protective effect on HXXO-induced gastric mucosal cell cytotoxi city through one or more of the following mechanism(s): (1) inhibition of lipid peroxidation of the cell membrane; (2) hydroxyl radical scav enging activity; and (3) induction of cellular cytoprotective protein such as HSP70. Copyright (C) 1997 Elsevier Science Inc.