Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749.
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.
Nagaya
H
H
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Satoh
H
H
Kubo
K
K
Maki
Y
Y
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004285:Dogs; D005033:Ethylmaleimide / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D064747:Lansoprazole; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D011522:Protons; D011725:Pyridines / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000032:analysis
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D011522:Protons; D011725:Pyridines; D013438:Sulfhydryl Compounds; D064747:Lansoprazole; C058689:AG 2000; C058688:AG 1812; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole; D005033:Ethylmaleimide; D004229:Dithiothreitol