Omeprazole, a specific inhibitor of gastric (H/sup +/-K/sup +/)-ATPase, is a H/sup +/-activated oxidizing agent of sulfhydryl groups
Omeprazole (5-methoxy-2-(((4-methoxy-3,5- dimethylpyridinyl)methyl)sulfinyl)-1H-benzimidazole) appeared to inhibit gastric (H/sup +/-K/sup +/)-ATPase by oxidizing its essential sulfhydryl groups, since the gastric ATPase inactivated by the drug in vivo or in vitro recovered its K+-dependent ATP hydrolyzing activity upon incubation with mercaptoethanol. Biological reducing agents like cysteine or glutathione, however, were unable to reverse the inhibitory effect of omeprazole. Moreover, acidic environments enhanced the potency of omeprazole. The chemical reactivity of omeprazole with mercaptans is also consistent with the biological action of omeprazole. The N-sulfenylated compound reacted at neutral pH with another stoichiometric amount of ethyl mercaptan to produce omeprazole sulfide quantitatively. The gastric polypeptides of 100 kilodaltons representing (H/sup +/-K/sup +/)-ATPase in the rat gastric mucosa or isolated hog gastric membranes were covalently labeled with (/sup 14/C)omeprazole. The radioactive label bound to the ATPase, however, could not be displaced by mercaptoethanol under the identical conditions where the ATPase activity was fully restored. These observations suggest that the essential sulfhydryl groups which reacted with omeprazole did not form a stable covalent bond with the drug, but rather that they further reacted with adjacent sulfhydryl groups to form disulfides which could be reduced by mercaptoethanol.
- Research Organization:
- Upjohn Co., Kalamazoo, MI
- OSTI ID:
- 5127783
- Journal Information:
- J. Biol. Chem.; (United States), Journal Name: J. Biol. Chem.; (United States) Vol. 8; ISSN JBCHA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ACID ANHYDRASES
ALKALI METAL COMPOUNDS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ATP-ASE
AZOLES
BARYONS
BENZIMIDAZOLES
BIOCHEMISTRY
CARBON 14 COMPOUNDS
CATIONS
CHARGED PARTICLES
CHEMICAL REACTIONS
CHEMISTRY
DOMESTIC ANIMALS
DRUGS
ELEMENTARY PARTICLES
ENZYME INHIBITORS
ENZYMES
FERMIONS
HADRONS
HETEROCYCLIC COMPOUNDS
HYDROLASES
IMIDAZOLES
IONS
KINETICS
LABELLED COMPOUNDS
MAGNETIC RESONANCE
MAMMALS
NUCLEAR MAGNETIC RESONANCE
NUCLEONS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
OXIDATION
PHOSPHOHYDROLASES
POTASSIUM COMPOUNDS
PROTONS
RATS
RESONANCE
RODENTS
SWINE
THIOLS
VALINOMYCIN
VERTEBRATES