Fryklund J, Gedda K, Wallmark B
Hässle Gastrointestinal Research Laboratories, Department of Biology, Mölndal, Sweden.
Biochem Pharmacol. 1988 Jul 1;37(13):2543-9. doi: 10.1016/0006-2952(88)90244-4.
Acid secretion is conducted by the parietal cell of the gastric mucosa. The H+,K+-ATPase has been shown to be specifically located to this cell and during recent years been recognized as the gastric proton pump. Omeprazole, a known inhibitor of acid secretion, administered in vivo was found to bind specifically to the H+,K+-ATPase of the rabbit gastric mucosa. A stoichiometry of 2.1 mol radiolabel per mol phosphoenzyme was calculated at total inhibition of the H+,K+-ATPase enzyme activity. In isolated gastric glands prepared from omeprazole-treated animals, the secretagogue-induced increase in oxygen consumption, related to acid secretion, was inhibited to the same level as the H+,K+-ATPase activity. Both the degree of acid secretion inhibition induced by omeprazole and the amount of inhibitor bound to the H+,K+-ATPase were found to be dependent on the stimulation state of the parietal cell. Inhibition of secretion by the H2-receptor blocker ranitidine prior to omeprazole treatment prevented both the inhibition of H+,K+-ATPase and oxygen consumption normally observed with omeprazole and, furthermore, reduced the binding levels of radiolabel to the enzyme. Inhibition of acid secretion by the H+,K+-ATPase inhibitor SCH 28080 totally prevented the binding of radiolabel to the H+,K+-ATPase. The inhibition by omeprazole could be fully reversed in gastric glands and H+,K+-ATPase isolated from omeprazole-treated animals by addition of beta-mercaptoethanol. The major product formed during reactivation was the reduced form of omeprazole, compound H 168/22. Neutralization of the gastric glands in vitro with imidazole totally prevented the inhibitory action of omeprazole. These experiments demonstrate the necessity of acid for the inhibition of gastric acid secretion by omeprazole and the binding of the inhibitor to the H+,K+-ATPase, both in vivo and in vitro, and also the specificity of omeprazole for the H+,K+-ATPase.
胃酸分泌由胃黏膜的壁细胞进行。H⁺，K⁺ - ATP酶已被证明特异性定位于该细胞，并且近年来被认为是胃质子泵。已知的胃酸分泌抑制剂奥美拉唑在体内给药时，被发现能特异性结合兔胃黏膜的H⁺，K⁺ - ATP酶。在H⁺，K⁺ - ATP酶活性完全被抑制时，计算出每摩尔磷酸化酶有2.1摩尔放射性标记的化学计量比。在从用奥美拉唑处理过的动物制备的离体胃腺中，与胃酸分泌相关的促分泌剂诱导的氧消耗增加被抑制到与H⁺，K⁺ - ATP酶活性相同的水平。发现奥美拉唑诱导的胃酸分泌抑制程度和与H⁺，K⁺ - ATP酶结合的抑制剂数量均取决于壁细胞的刺激状态。在奥美拉唑治疗前用H₂受体阻滞剂雷尼替丁抑制分泌，可防止通常用奥美拉唑观察到的H⁺，K⁺ - ATP酶和氧消耗的抑制，此外，还降低了放射性标记与该酶的结合水平。H⁺，K⁺ - ATP酶抑制剂SCH 28080抑制胃酸分泌完全阻止了放射性标记与H⁺，K⁺ - ATP酶的结合。通过添加β - 巯基乙醇，奥美拉唑在离体胃腺和从用奥美拉唑处理过的动物分离的H⁺，K⁺ - ATP酶中的抑制作用可完全逆转。再激活过程中形成的主要产物是奥美拉唑的还原形式，即化合物H 168/22。用咪唑在体外中和胃腺完全阻止了奥美拉唑的抑制作用。这些实验证明了胃酸对于奥美拉唑在体内和体外抑制胃酸分泌以及抑制剂与H⁺，K⁺ - ATP酶结合的必要性，同时也证明了奥美拉唑对H⁺，K⁺ - ATP酶的特异性。
