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 antithyroid drug of thionamide group, induces gastric acid secretion at least partially through the liberation of histamine, sensitive to cimetidine. Now, we show that the drug has a significant inhibitory effect on the cyclooxygenase and peroxidase activity of the prostaglandin (PG) synthetase of the gastric mucosal microsomal preparation. The effect can also be mimicked by low concentrations of H2O2. While studying the possible intracellular effect of MMI on acid secretion, a cell fraction (F3) 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 O2 consumption. The activation is sensitive to omeprazole, a proton-pump inhibitor, indicating that the activation is due to increased acid secretion by MMI. MMI was also found to directly inhibit the peroxidase activity of the F3 cell fraction and may thus increase the intracellular level of H2O2. The cyclooxygenase activity of the PG synthetase of the F3 cell fraction is also inhibited by MMI and the effect can be reproduced by low concentrations of H2O2. Both MMI and H2O2 can also inhibit the peroxidase activity of the PG synthetase. We suggest that in addition to the activation of the parietal cell by MMI possibly through endogenous H2O2, MMI induces acid secretion in vivo by inactivating the PG synthetase thereby inhibiting the biosynthesis of PG and removing its inhibitory influence on acid secretion so that the histamine released by MMI can stimulate acid secretion with maximum efficiency.
Bhattacharjee
M
M
Department of Physiology, Indian Institute of Chemical Biology, Calcutta.
Chakraborty
T
T
Ganguly
C
C
Banerjee
R K
RK
D000818:Animals; D002458:Cell Fractionation; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000737:chemistry / Q000201:enzymology; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*
C107674:2-mercapto-1-methylimidazole; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D006861:Hydrogen Peroxide; D009195:Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases