Possible mechanism for the inhibition of acid formation by the proton pump inhibitor AG-1749 in isolated canine parietal cells.
We have reported previously that 2-[[[3-methyl-4-(2,2,2-trifluorethoxy)-2-pyridyl]methyl] sulfinil]- 1H-benzimidazole (AG-1749) inhibits (H+ + K+)-adenosine triphosphatase after being transformed into its cyclic sulfenamide form (AG-2000) or disulfide form (AG-1812) under acidic conditions. In this study, mechanisms related to the inhibition of acid formation by AG-1749 were investigated in isolated canine parietal cells. AG-1749 suppressed the acid formation stimulated by histamine, carbachol or dibutyryl cyclic AMP with IC50 values of approximately 0.09 microM: AG-1749 being twice as potent as omeprazole. The inhibitory effect of AG-1749 was antagonized by dithiothreitol (1 mM). 2-Cyclo-hexen-1-one (3 mM) decreased cytosolic glutathione to less than 10% of control value, and caused a 3-fold increase in the inhibitory effect of AG-1749. Glutathione, however, when added exogenously, did not affect the action of AG-1749. The inhibition was reversed by removing AG-1749 from the medium or by adding dithiothreitol (1 mM). The reversal of inhibition by these two procedures was hardly affected by puromycin (100 microM) or cycloheximide (300 microM) but significantly prevented by 2-cyclo-hexen-1-one (1 mM). Exogenously added AG-2000 (10 microM) or AG-1812 (5 microM), active forms of AG-1749, did not inhibit acid formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Nagaya
H
H
Research & Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Satoh
H
H
Maki
Y
Y
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors*; D000818:Animals; D003994:Bucladesine / Q000037:antagonists & inhibitors; D002217:Carbachol / Q000037:antagonists & inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D006633:Histamine Antagonists / Q000494:pharmacology; D064747:Lansoprazole; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects* / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D006633:Histamine Antagonists; D064747:Lansoprazole; D011691:Puromycin; D003994:Bucladesine; D011899:Ranitidine; D000255:Adenosine Triphosphate; D002217:Carbachol; D003513:Cycloheximide; D009853:Omeprazole