Larsson H, Håkanson R, Mattsson H, Ryberg B, Sundler F, Carlsson E
Department of Biology, AB Hässle, Mölndal, Sweden.
Toxicol Pathol. 1988;16(2):267-72. doi: 10.1177/019262338801600220.
The H+,K+-ATPase inhibitor omeprazole is a highly effective gastric antisecretory agent, both in animals and man, with a long duration of action. These properties are shared by a number of recently described histamine H2-receptor antagonists. In life-long oncogenicity studies of these H2-receptor antagonists, as well as with the H+,K+-ATPase inhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasia and carcinoids have been found. The purpose of this paper is to summarize available evidence for the "Gastrin Hypothesis" to explain the development of ECL-cell hyperplasia. The hypothesis may be outlined as follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release of gastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of the oxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occurs not only with omeprazole but also with other effective gastric antisecretory agents has been verified in the rat by giving the H2-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergastrinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibited to a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed during both ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasia during omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, but rather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to be reversible.(ABSTRACT TRUNCATED AT 250 WORDS)
H⁺，K⁺ -ATP酶抑制剂奥美拉唑是一种在动物和人类中均具有高效且作用持久的胃抗分泌剂。许多最近描述的组胺H₂受体拮抗剂也具有这些特性。在对这些H₂受体拮抗剂以及H⁺，K⁺ -ATP酶抑制剂奥美拉唑的终生致癌性研究中，发现了胃嗜铬样细胞（ECL细胞）增生和类癌。本文的目的是总结“胃泌素假说”的现有证据，以解释ECL细胞增生的发生。该假说可概述如下：1）胃酸分泌的抑制导致胃窦pH值升高，继而导致胃窦胃泌素细胞释放胃泌素进入血流。2）胃泌素导致胃体黏膜普遍肥大以及胃体黏膜中ECL细胞增生。通过持续输注H₂受体拮抗剂雷尼替丁，已在大鼠中证实，不仅奥美拉唑，其他有效的胃抗分泌剂也会发生这一系列事件。如果胃酸分泌被抑制到相似程度，雷尼替丁引起的高胃泌素血症与奥美拉唑后的相似。在相似的胃泌素水平下，雷尼替丁和奥美拉唑治疗期间均出现了相同程度的ECL细胞增生。胃窦切除术可防止奥美拉唑治疗期间ECL细胞增生的发生，这表明增生并非由于药物治疗本身，而是由于高胃泌素血症。高胃泌素血症和ECL细胞增生均被发现是可逆的。（摘要截短至250字）
