Tamai H, Kachur J F, Grisham M B, Gaginella T S
Gastrointestinal Diseases Research, Searle Research and Development, Skokie, IL 60077.
Biochem Pharmacol. 1991;41(6-7):1001-6. doi: 10.1016/0006-2952(91)90207-l.
Inflammatory phagocytic leukocytes produce superoxide and hydrogen peroxide and secrete myeloperoxidase (MPO) into the extracellular medium. MPO catalyzes the oxidation of Cl- by H2O2 to yield chlorinated oxidants (e.g. HOCl and NH2Cl), which have been shown to induce pathologic changes in mucosal function. We examined the ability of 5-aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease (IBD), to inhibit oxidation of L-cysteine by NH2Cl, HOCl and H2O2. NH2Cl and HOCl were especially strong oxidants against L-cysteine. 5-ASA prevented L-cysteine oxidation by NH2Cl and HOCl; an interaction associated with the formation of characteristic absorption spectra due to the oxidation of 5-ASA was observed. NH2Cl and HOCl evoked characteristic increases in short-circuit current (Isc), indicative of net electrolyte transport, when added to the serosal side of stripped rat colon mounted in Ussing chambers. Premixing of NH2Cl with 5-ASA 10 min before addition to the tissue markedly reduced the secretory response to NH2Cl. In contrast, 5-ASA immediately reduced the response to HOCl. The reduction in the functional response to NH2Cl and HOCl by 5-ASA may contribute to its mechanism of action in the treatment of the symptoms of IBD.
炎性吞噬白细胞产生超氧化物和过氧化氢，并将髓过氧化物酶（MPO）分泌到细胞外介质中。MPO催化H2O2氧化Cl-生成氯化氧化剂（如HOCl和NH2Cl），这些氧化剂已被证明可诱导黏膜功能发生病理变化。我们研究了用于治疗炎性肠病（IBD）的药物5-氨基水杨酸（5-ASA）抑制NH2Cl、HOCl和H2O2对L-半胱氨酸氧化的能力。NH2Cl和HOCl对L-半胱氨酸是特别强的氧化剂。5-ASA可防止NH2Cl和HOCl氧化L-半胱氨酸；观察到由于5-ASA氧化而形成特征吸收光谱的相互作用。当将NH2Cl添加到安装在尤斯灌流小室中的剥离大鼠结肠浆膜侧时，可引起短路电流（Isc）特征性增加，表明有净电解质转运。在添加到组织前10分钟将NH2Cl与5-ASA预混合可显著降低对NH2Cl的分泌反应。相比之下，5-ASA可立即降低对HOCl的反应。5-ASA对NH2Cl和HOCl功能反应的降低可能有助于其治疗IBD症状的作用机制。
