Mechanism of inhibition of H+, K(+)-ATPase by sodium 2-[[4-(3- methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1H-benzimidazole (E3810).
Sodium 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl ]- 1H-benzimidazole (E3810) and omeprazole inhibit gastric acid secretion through inhibition of the activity of H+, K(+)-ATPase present in parietal cell membrane vesicles, by chemical modification of SH groups in the enzyme molecule. In order to clarify the mechanism of the chemical modification, reaction products of E3810 and omeprazole with 2-mercaptoethanol under acidic conditions (pH 3, 4, 5, 6) were isolated by HPLC, and subjected to structural analysis by UV, 1H-NMR and mass spectrometry. E3810 and omeprazole appeared to undergo two kinds of reactions, affording disulfide-type products (type I reaction) and sulfide-type products (type II reaction). The rates of these reactions were determined by HPLC, and the stability of the products in the presence and absence of glutathione was investigated. In the case of E3810, type I reaction was found to proceed faster than type II reaction at every pH value studied. The type I reaction of E3810 was faster than that of omeprazole. The rate of type I reaction decreased at pH 5 and 6, especially for omeprazole, and the contribution of type II reaction increased as the pH of the reaction mixture was increased. The sulfide-type modification products were stable, whereas the formation of the disulfide-type modification products was reversed by the action of endogenous SH compounds such as glutathione. These results suggest that higher inhibitory activity of E3810 against gastric acid secretion and faster recovery of the enzyme activity after inhibition by E3810 can be expected, as compared with those of omeprazole.
Nochi
S
S
Tsukuba Research Laboratories, Eisai Co., Ltd., Japan.
Yokoyama
Y
Y
Narukawa
M
M
Ebine
K
K
Murahashi
M
M
Kawakami
Y
Y
Asakawa
N
N
Sato
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000737:chemistry; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry; D008623:Mercaptoethanol / Q000737:chemistry / Q000494:pharmacology; D009853:Omeprazole / Q000737:chemistry / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D013438:Sulfhydryl Compounds / Q000737:chemistry; D047392:beta-Cyclodextrins
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D003505:Cyclodextrins; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D013438:Sulfhydryl Compounds; D047392:beta-Cyclodextrins; D064750:Rabeprazole; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; D008623:Mercaptoethanol; D017506:H(+)-K(+)-Exchanging ATPase; D005978:Glutathione; D009853:Omeprazole