RT Journal Article
SR Electronic
T1 Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 799
OP 805
VO 248
IS 2
A1 Nagaya, H
A1 Satoh, H
A1 Kubo, K
A1 Maki, Y
YR 1989
UL http://jpet.aspetjournals.org/content/248/2/799.abstract
AB 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 [14C]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.