van Zyl J M, Kriegler A, van der Walt B J
Department of Pharmacology, Medical School, University of Stellenbosch, Tygerberg, South Africa.
Biochem Pharmacol. 1993 Jun 22;45(12):2389-97. doi: 10.1016/0006-2952(93)90218-l.
Ulcerogenesis of the gastroduodenal mucosa is caused by the digestive action of gastric juice and initially involves an inflammatory reaction with infiltration of phagocytes. The anti-inflammatory activity of many drugs have been attributed to the inhibition of the leukocyte enzyme, myeloperoxidase (MPO). In this study, the H2-antagonists in clinical use were found to be potent inhibitors of MPO-catalysed reactions (IC50 < 3 microM) under conditions resembling those in experiments with intact neutrophils. Since peak plasma concentrations of cimetidine, ranitidine and nizatidine are well within the micromolar range, after oral therapeutic dosing, our results may be of clinical relevance. The inhibitory actions of cimetidine and nizatidine were largely due to scavenging of hypochlorous acid (HOCl), a powerful chlorinating oxidant produced in the MPO-H2O2-Cl- system. In contrast to famotidine, ranitidine was also a potent scavenger of HOCl, while both drugs inhibited MPO reversibly by converting it to compound II, which is inactive in the oxidation of Cl-. The HOCl scavenging potencies of ranitidine and nizatidine were about three times higher than that of the anti-rheumatic drug, penicillamine, which had a potency similar to that of cimetidine. The rapid HOCl scavenging ability of penicillamine is thought to contribute to its anti-inflammatory effects. Using riboflavin as a probe, the H2-antagonists were found to be inhibitors of hydroxyl radical (.OH) generated in a Fe(2+)-H2O2 reaction mixture. Spectral analyses of the interaction of iron ions with the drugs and studies with chelators, suggest that the drugs were efficient chelators of Fe2+, in addition to their .OH scavenging abilities. Since the gastrointestinal tract can contain potentially reactive iron, the simultaneous presence of H2-antagonists may help to suppress iron-driven steps in tissue damage.
胃十二指肠黏膜溃疡的形成是由胃液的消化作用引起的，最初涉及吞噬细胞浸润的炎症反应。许多药物的抗炎活性归因于对白细胞酶髓过氧化物酶（MPO）的抑制作用。在本研究中，发现在类似于完整中性粒细胞实验的条件下，临床使用的H2拮抗剂是MPO催化反应的有效抑制剂（IC50 < 3 microM）。由于西咪替丁、雷尼替丁和尼扎替丁的血浆峰值浓度在口服治疗给药后完全处于微摩尔范围内，我们的结果可能具有临床相关性。西咪替丁和尼扎替丁的抑制作用主要是由于清除了次氯酸（HOCl），次氯酸是MPO-H2O2-Cl-系统中产生的一种强大的氯化氧化剂。与法莫替丁不同，雷尼替丁也是HOCl的有效清除剂，而这两种药物通过将MPO转化为化合物II来可逆地抑制MPO，化合物II在Cl-的氧化中无活性。雷尼替丁和尼扎替丁的HOCl清除能力比抗风湿药物青霉胺高约三倍，青霉胺的清除能力与西咪替丁相似。青霉胺快速清除HOCl的能力被认为有助于其抗炎作用。以核黄素为探针，发现H2拮抗剂是Fe(2+)-H2O2反应混合物中产生的羟基自由基（·OH）的抑制剂。铁离子与药物相互作用的光谱分析以及螯合剂研究表明，这些药物除了具有清除·OH的能力外，还是Fe2+的有效螯合剂。由于胃肠道可能含有潜在的活性铁，H2拮抗剂的同时存在可能有助于抑制组织损伤中铁驱动的步骤。
