Interaction of the anti-inflammatory seleno-organic compound ebselen with acid secretion in isolated parietal cells and gastric H+/K(+)-ATPase.
The effects of the anti-inflammatory seleno-organic compound ebselen on gastric H+/K(+)-ATPase, H+/K(+)-ATPase-mediated proton transport and on parietal cell HCl production was studied. Ebselen inhibited K(+)-stimulated ATPase activity in leaky gastric membranes (IC50:0.15 microM) and H+/K(+)-ATPase-mediated proton transport in intact gastric membrane vesicles (IC50:0.7 microM). Histamine- and dibutyryl-cAMP-stimulated HCl production in isolated and enriched guinea-pig parietal cells was inhibited with an IC50 value of 12 microM. The mercaptan dithioerythritol and the nucleotide ATP prevents the H+/K(+)-ATPase against inactivation and dithioerythritol was found to restore already inhibited enzyme activity and ATPase mediated H+ transport. Furthermore, dithioerythritol could prevent ebselen-induced inhibition of HCl production in the parietal cell preparation. It is concluded that ebselen inhibits acid secretion in the parietal cell by interference with SH groups of the gastric proton pump, the H+/K(+)-ATPase. Therefore ebselen can be regarded as an anti-inflammatory drug for which in vitro anti-secretory properties can be demonstrated.
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Abteilung Allgemeine Pharmakologie, Medizinische Hochschule, Hannover, Federal Republic of Germany.
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D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D006168:Guinea Pigs; D017506:H(+)-K(+)-Exchanging ATPase; D054833:Isoindoles; D007668:Kidney / Q000201:enzymology; D016566:Organoselenium Compounds; D010295:Parietal Cells, Gastric / Q000187:drug effects* / Q000378:metabolism; D011522:Protons; D012643:Selenium / Q000494:pharmacology*; D013270:Stomach / Q000201:enzymology*; D013552:Swine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D011522:Protons; C042986:ebselen; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D012643:Selenium