Mechanism of Inhibition of H+, K+-ATPase by Sodium 2-((4-(3-Methoxypropoxy)-3-methylpyridin-2-yl)methylsulfinyl)-lH- benzimidazole (E3810).
作者:Shigeharu NOCHI、Yumi YOKOYAMA、Megumi NARUKAWA、Kumiko EBINE、Miho MURAHASHI、Yoshiyuki KAWAKAMI、Naoki ASAKAWA、Tadashi SATO
DOI:10.1248/cpb.44.552
日期:——
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 comeprazole. 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 facter recovery of the enzyme activity after inhibition by E3810 can be expencted, as compared with those of omeprazole.
2-[[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚磺酰基]-1H-苯并咪唑钠(E3810)和奥美拉唑通过抑制壁细胞膜囊泡中H+、K+-ATP酶的活性来抑制胃酸分泌,其作用机理是化学修饰酶分子中的SH基团。为了阐明化学修饰的机理,通过HPLC分离了E3810和奥美拉唑与2-巯基乙醇在酸性条件(pH 3、4、5、6)下的反应产物,并通过紫外光谱、1H-NMR和质谱对其进行了结构分析。E3810和奥美拉唑似乎经历了两种反应,产生了二硫键型产物(I型反应)和硫键型产物(II型反应)。通过HPLC测定了这些反应的速率,并研究了产物在有和没有谷胱甘肽时的稳定性。就E3810而言,在研究的每个pH值下,I型反应都比II型反应进行得快。E3810的I型反应比奥美拉唑的I型反应快。在pH 5和6时,I型反应的速率降低,特别是对于奥美拉唑而言,并且随着反应混合物的pH升高,II型反应的贡献增加。硫键型