EFFECT OF OMEPRAZOLE ON SECRETION, SYNTHESIS AND THE GENE-EXPRESSION OF PEPSINOGEN IN THE GUINEA-PIG STOMACH MUCOSA

The effects of omeprazole, a proton pump inhibitor, on gene expression , protein synthesis, intracellular storage and secretion of pepsinogen in guinea pig stomach were investigated. After treatment with omepraz ole for five days, acid and pepsinogen secretion into the gastric lume n was significantly reduced. Concomitant with this, there was an incre ase in intracellular pepsinogen as demonstrated by increased pepsin ac tivity in the gastric mucosa, more intense immunohistochemical stainin g by antibodies specific for pepsinogen and accumulation of secretory granules in the cells producing pepsinogen. In these cells, the amount of pepsinogen mRNA was reduced as revealed by Northern blotting and i n situ hybridization. Ultrastructurally the endoplasmic reticulum of t hese cells was poorly developed, the findings being consistent with a reduction in protein synthesis. It appears that omeprazole inhibits th e secretion of pepsinogen, increasing the intracellular store and lead ing to the reduction in gene expression probably by a feedback mechani sm and consequent reduction in pepsinogen synthesis. Since these chang es were most evident in the acid-secreting fundic gland mucosa, as com pared with other mucosae secreting only pepsinogen, namely pyloric and duodenal mucosa, it appears probable that these changes are linked wi th omeprazole-induced reduction in the acid secretion.