Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749
Journal Article
·
· J. Pharmacol. Exp. Ther.; (United States)
OSTI ID:6327088
Mechanisms related to the inhibition of (H+ + K+)-adenosine triphosphatase (ATPase) by 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl) sulfinyl)-1H-benzimidazole (AG-1749) were studied using canine gastric microsomes. AG-1749 (1-100 microM) inhibited the K+-stimulated ATP hydrolysis and vesicular accumulation of H+. AG-1749 bound to the microsomes concentration-dependently and decreased the number of free SH groups; the binding correlating with the enzyme inhibition. Both the binding and inhibition were antagonized by dithiothreitol. N-ethylmaleimide inhibited the (H+ + K+)-ATPase and decreased the binding of (/sup 14/C)AG-1749 to the microsomes. The inhibitory effect of AG-1749 gradually increased with incubation time, and was enhanced by lowering the pH. AG-2000 and AG-1812, acid-induced rearrangement products of AG-1749, inhibited (H+ + K+)-ATPase potently, rapidly and independently of pH; the inhibition was antagonized by dithiothreitol. We propose that AG-1749 is transformed into its active forms within the acidic compartment of the parietal cells and that the active compounds inhibit (H+ + K+)-ATPase activity by reacting with the SH groups of the enzyme.
- Research Organization:
- Takeda Chemical Industries, Ltd., Osaka (Japan)
- OSTI ID:
- 6327088
- Journal Information:
- J. Pharmacol. Exp. Ther.; (United States), Journal Name: J. Pharmacol. Exp. Ther.; (United States) Vol. 248:2; ISSN JPETA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ACID ANHYDRASES
ANIMALS
ATP
ATP-ASE
AZINES
AZOLES
BARYONS
BENZIMIDAZOLES
BIOCHEMICAL REACTION KINETICS
CARBON 14 COMPOUNDS
CELL CONSTITUENTS
DIGESTIVE SYSTEM
DOGS
ELEMENTARY PARTICLES
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
FERMIONS
GASTROINTESTINAL TRACT
HADRONS
HETEROCYCLIC COMPOUNDS
HYDROLASES
IMIDAZOLES
IN VITRO
INHIBITION
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MICROSOMES
NUCLEONS
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANOIDS
PHOSPHOHYDROLASES
PROTONS
PYRIDINES
REACTION KINETICS
TRACER TECHNIQUES
VERTEBRATES
59 BASIC BIOLOGICAL SCIENCES
ACID ANHYDRASES
ANIMALS
ATP
ATP-ASE
AZINES
AZOLES
BARYONS
BENZIMIDAZOLES
BIOCHEMICAL REACTION KINETICS
CARBON 14 COMPOUNDS
CELL CONSTITUENTS
DIGESTIVE SYSTEM
DOGS
ELEMENTARY PARTICLES
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
FERMIONS
GASTROINTESTINAL TRACT
HADRONS
HETEROCYCLIC COMPOUNDS
HYDROLASES
IMIDAZOLES
IN VITRO
INHIBITION
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MICROSOMES
NUCLEONS
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANOIDS
PHOSPHOHYDROLASES
PROTONS
PYRIDINES
REACTION KINETICS
TRACER TECHNIQUES
VERTEBRATES