Uetrecht J P, Shear N H, Zahid N
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Drug Metab Dispos. 1993 Sep-Oct;21(5):830-4.
It is known that activation of neutrophils or monocytes leads to the formation of hydrogen peroxide and the release of myeloperoxidase (MPO). We found that sulfamethoxazole was chlorinated by the combination of MPO, hydrogen peroxide, and chloride. The product, N-chlorosulfamethoxazole, is reasonably stable but reacts rapidly with a variety of compounds. The same product was formed by the reaction between sulfamethoxazole and hypochlorous acid, and dapsone was also N-chlorinated by the MPO system or hypochlorous acid. Although N-chlorination was not observed when sulfamethoxazole or dapsone was incubated with activated neutrophils, this is presumably because the chloramine products react rapidly with the cells. When radiolabeled sulfamethoxazole was incubated with activated neutrophils, covalent binding was observed. When radiolabeled sulfamethoxazole was incubated with MPO and hydrogen peroxide in the presence of albumin, covalent binding to the albumin occurred. Although binding to albumin occurred in the absence of chloride, it was increased by the presence of chloride. This suggests that N-chlorosulfamethoxazole may be one of several reactive metabolites of sulfamethoxazole that covalently bind to neutrophils. We suspect that covalent binding of arylamine drugs, such as sulfamethoxazole, to activated leukocytes is responsible for some of the adverse reactions associated with these drugs, especially adverse reactions that involve leukocytes such as agranulocytosis or drug-induced lupus.
已知中性粒细胞或单核细胞的激活会导致过氧化氢的形成和髓过氧化物酶（MPO）的释放。我们发现，磺胺甲恶唑会被MPO、过氧化氢和氯离子共同作用而氯化。产物N-氯磺胺甲恶唑相当稳定，但能与多种化合物迅速反应。磺胺甲恶唑与次氯酸反应也会生成相同的产物，氨苯砜也会被MPO系统或次氯酸进行N-氯化。虽然磺胺甲恶唑或氨苯砜与活化的中性粒细胞一起孵育时未观察到N-氯化现象，但推测这是因为氯胺产物会与细胞迅速反应。当放射性标记的磺胺甲恶唑与活化的中性粒细胞一起孵育时，会观察到共价结合。当放射性标记的磺胺甲恶唑在白蛋白存在的情况下与MPO和过氧化氢一起孵育时，会发生与白蛋白的共价结合。虽然在没有氯离子的情况下也会发生与白蛋白的结合，但有氯离子存在时结合会增加。这表明N-氯磺胺甲恶唑可能是磺胺甲恶唑几种与中性粒细胞共价结合的反应性代谢产物之一。我们怀疑芳胺类药物，如磺胺甲恶唑，与活化白细胞的共价结合是这些药物相关的一些不良反应的原因，尤其是涉及白细胞的不良反应，如粒细胞缺乏症或药物性狼疮。
