Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749.
Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749.
复制标题
质子泵抑制剂 AG-1749 抑制胃 (HK)-三磷酸腺苷酶的可能机制。
DOI：
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发表时间：
1989
影响因子：
3.5
通讯作者：
Y. Maki
中科院分区：
文献类型：
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作者：
H. Nagaya;H. Satoh;K. Kubo;Y. Maki
用犬胃微粒体研究了2-[[[3-methyl-4-(2，2，2-trifluoroethoxy)-2-pyridyl]methyl]-1H-苯并咪唑(AG-1749)抑制(H++K+)-三磷酸腺苷酶(ATPase)的作用机制。AG-1749(1-100微米)抑制K+刺激的ATP水解和H+的囊泡积累。AG-1749与微粒体的结合呈浓度依赖关系，减少了游离SH基团的数目；这种结合与酶抑制有关。二硫苏糖醇可拮抗这种结合和抑制作用。N-乙基马来酰亚胺抑制(H++K+)-ATPase，降低[14C]AG-1749与微粒体的结合。AG-1749的抑制作用随孵育时间的延长而逐渐增强，并随pH的降低而增强。AG-1749的酸性重排产物AG-2000和AG-1812对(H++K+)-ATPase有明显的抑制作用，且抑制作用不依赖于pH，这种抑制作用可被二硫苏糖醇拮抗。我们认为AG-1749在壁细胞的酸性隔室内转化为活性形式，活性化合物通过与酶的SH基团反应抑制(H++K+)-ATPase活性。
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.