INHIBITION OF GASTRIC-MUCOSAL PROSTAGLANDIN SYNTHETASE-ACTIVITY BY MERCAPTOMETHYLIMIDAZOLE, AN INDUCER OF GASTRIC-ACID SECRETION - PLAUSIBLE INVOLVEMENT OF ENDOGENOUS H2O2

We have reported earlier that mercaptomethylimidazole (MMI), an antith yroid drug of thionamide group, induces gastric acid secretion at leas t partially through the liberation of histamine, sensitive to cimetidi ne. Now, we show that the drug has a significant inhibitory effect on the cyclooxygenase and peroxidase activity of the prostaglandin (PG) s ynthetase of the gastric mucosal microsomal preparation. The effect ca n also be mimicked by low concentrations of H2O2. While studying the p ossible intracellular effect of MMI on acid secretion, a cell fraction (F-3) enriched in parietal cell was isolated by controlled digestion of the mucosa with protease. This cell fraction is activated by MMI as measured by increased O-2 consumption. The activation is sensitive to omeprazole, a proton-pump inhibitor, indicating that the activation i s due to increased acid secretion by MMI. MMI was also found to direct ly inhibit the peroxidase activity of the F-3 cell fraction and may th us increase the intracellular level of H2O2. The cyclooxygenase activi ty of the PG synthetase of the F-3 cell fraction is also inhibited by MMI and the effect can be reproduced by low concentrations of H2O2. Bo th MMI and H2O2 can also inhibit the peroxidase activity of the PG syn thetase. We suggest that in addition to the activation of the parietal cell by MMI possibly through endogenous H2O2, MMI induces acid secret ion in vivo by inactivating the PG synthetase thereby inhibiting the b iosynthesis of PG and removing its inhibitory influence on acid secret ion so that the histamine released by MMI can stimulate acid secretion with maximum efficiency. BIOCHEM PHARMACOL 56;7:905-913, 1998. (C) 19 98 Elsevier Science Inc.