title: Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777.
abstract: Atrophic gastritis, characterized as parietal cell loss or oxyntic atrophy, is the primary event in the evolution of the spectrum of metaplastic and hyperplastic lineage changes thought to predispose to gastric neoplasia. A number of animal models have provided insights into the lineage changes induced by oxyntic atrophy. Recently, we have reported a model for pharmacological induction of oxyntic atrophy with DMP-777. DMP-777 ablates parietal cells selectively and leads to the gastric cell lineage changes including foveolar hyperplasia and spasmolytic polypeptide expressing metaplasia (SPEM). Previous investigations showed that DMP-777 dissipated a gastric tubulovesicle proton gradient without impairing the H/K-ATPase activity, consistent with its pharmacological action as a parietal cell-specific protonophore which could induce parietal cell necrosis through backwash of luminal acid into actively secreting cells. We hypothesized that, if DMP-777 was acting as a parietal cell protonophore, then suppression of acid secretion should protect parietal cells from the toxic effects of the drug. In this study, we pretreated and coadministered the proton pump inhibitor omeprazole with DMP-777 to determine the effect of active acid secretion inhibition on the DMP-777-induced histologic changes in the stomachs of male rats. Omeprazole pretreatment ameliorated DMP-777-induced parietal cell loss as well as foveolar hyperplasia. These results indicate that active acid secretion is required for DMP-777 cytotoxicity, consistent with its suggested behavior as a parietal cell-specific protonophore.
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2733, USA.
authors.forename: Masako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Nomura
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Car
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001384:Azetidines; D004195:Disease Models, Animal; D004347:Drug Interactions; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D005757:Gastritis, Atrophic / Q000188:drug therapy* / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D009853:Omeprazole / Q000494:pharmacology*; D010295:Parietal Cells, Gastric / Q000187:drug effects* / Q000473:pathology; D010879:Piperazines; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D000071164:Trefoil Factor-2
chemical_list: D001384:Azetidines; D010879:Piperazines; C000604008:Tff2 protein, rat; D000071164:Trefoil Factor-2; C105999:DMP 777; D009853:Omeprazole