Restoration of acid secretion following treatment with proton pump inhibitors
Restoration of acid secretion following treatment with proton pump inhibitors
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DOI：
10.1053/gast.2002.36593
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发表时间：
2002-11-01
期刊：
影响因子：
29.4
通讯作者：
Sachs, G
中科院分区：
文献类型：
--
作者：
Shin, JM;Sachs, G
背景和目标：质子泵抑制剂（PPI）是胃H+，K+-腺苷三磷酸酶（ATP酶）形成二硫键的共价抑制剂。PPI抑制后酸分泌的恢复可能是由于泵蛋白的重新合成和/或二硫键还原和受抑制泵的重新激活。奥美拉唑治疗后大鼠酸分泌恢复的半衰期类似于15小时，而泵蛋白半衰期为54小时。在人体中，奥美拉唑对胃酸分泌的抑制作用的半衰期与28小时相似，泮托拉唑与46小时相似。尽管所有PPI都与半胱氨酸813结合，但泮托拉唑还与TM 6膜结构域更深处的半胱氨酸822结合。由于二硫键对谷胱甘肽的可及性不同，它们的不同作用持续时间可能反映了泵重新激活的不同速率。方法：用30 mg/kg的PPI刺激和处理大鼠。制备胃ATP酶，并通过与二硫苏糖醇或谷胱甘肽孵育来测量H+，K+-ATP酶抑制的逆转，作为活性的时间依赖性恢复。结果如下：二硫苏糖醇和谷胱甘肽在体内被奥美拉唑或其对映体抑制后，ATP酶的再活化率分别为100%和89%。兰索拉唑或雷贝拉唑的数据相似。在泮托拉唑抑制后，未观察到任何还原剂的再活化。结论：除泮托拉唑外，所有PPI抑制后酸分泌的恢复可能取决于蛋白质转换和抑制性二硫键的逆转。相反，泮托拉唑后酸分泌的恢复可能完全取决于新蛋白质的合成。
Background & Aims: Proton pump inhibitors (PPIs) are covalent inhibitors of the gastric H+,K+-adenosine triphosphatase (ATPase) forming disulfide bonds. Recovery of acid secretion after PPI inhibition may be due to de novo synthesis of pump protein and/or disulfide reduction and reactivation of inhibited pump. The half-time of recovery of acid secretion in rats following omeprazole treatment is similar to15 hours, whereas pump protein half-life is 54 hours. In humans, the half-life of the inhibitory effect on acid secretion is similar to28 hours for omeprazole and similar to46 hours for pantoprazole. Whereas all PPIs bind to cysteine 813, pantoprazole additionally binds to cysteine 822, deeper in the membrane domain of TM6. Their different durations of action may reflect different rates of pump reactivation due to differing accessibility of the disulfides to glutathione. Methods: Rats were stimulated and treated with 30 mg/kg of each PPI. Gastric ATPase was prepared and reversal of inhibition of the H+,K+-ATPase was measured as the time-dependent restoration of activity by incubation with dithiothreitol or glutathione. Results: One hundred percent reactivation of ATPase following inhibition in vivo by omeprazole or its enantiomers was seen with dithiothreitol and 89% with glutathione. Similar data were found for lansoprazole or rabeprazole. No reactivation by either reducing agent was seen following inhibition by pantoprazole. Conclusions: Recovery of acid secretion following inhibition by all PPIs, other than pantoprazole, may depend on both protein turnover and reversal of the inhibitory disulfide bond. In contrast, recovery of acid secretion after pantoprazole may depend entirely on new protein synthesis.