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.