Department of Paediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
J Clin Pharmacol. 2020 Mar;60(3):409-421. doi: 10.1002/jcph.1535. Epub 2019 Nov 10.
Antimicrobial sulfonamides are important medications. However, their use is associated with major immune-mediated drug hypersensitivity reactions with a rate that ranges from 3% to 4% in the general population. The pathophysiology of sulfa-induced drug hypersensitivity reactions is not well understood, but accumulation of reactive metabolites (sulfamethoxazole [SMX] hydroxylamine [SMX-HA] and SMX N-nitrosamine [SMX-NO]) is thought to be a major factor. These reactive metabolites contribute to the formation of reactive oxygen species (ROS) known to cause cellular damage and induce cell death through apoptosis and necroptosis. ROS can also serve as "danger signals," priming immune cells to mount an immunological reaction. We recruited 26 sulfa-hypersensitive (HS) patients, 19 healthy control subjects, and 6 sulfa-tolerant patients to this study. Peripheral blood monocytes and platelets were isolated from blood samples and analyzed for in vitro cytotoxicity, ROS and carbonyl protein formation, lipid peroxidation, and GSH (glutathione) content after challenge with SMX-HA. When challenged with SMX-HA, cells isolated from sulfa-HS patients exhibited significantly (P ≤ .05) higher cell death, ROS and carbonyl protein formation, and lipid peroxidation. In addition, there was a high correlation between cell death in PBMCs and ROS levels. There was also depletion of GSH and lower GSH/GSSG ratios in peripheral blood mononuclear cells from sulfa-HS patients. The amount of ROS formed was negatively correlated with intracellular GSH content. The data demonstrate a major role for oxidative stress in in vitro cytotoxicity of SMX reactive metabolites and indicate increased vulnerability of cells from sulfa-HS patients to the in vitro challenge.
抗菌磺胺类药物是重要的药物。然而，它们的使用与主要的免疫介导的药物超敏反应有关，在普通人群中的发生率为 3%至 4%。磺胺类药物引起的药物超敏反应的病理生理学机制尚不清楚，但活性代谢物（磺胺甲恶唑[SMX]羟胺[SMX-HA]和 SMX N-亚硝胺[SMX-NO]）的积累被认为是一个主要因素。这些活性代谢物有助于形成活性氧（ROS），已知 ROS 会导致细胞损伤，并通过细胞凋亡和坏死引起细胞死亡。ROS 还可以作为“危险信号”，启动免疫细胞引发免疫反应。我们招募了 26 名磺胺类药物超敏（HS）患者、19 名健康对照者和 6 名磺胺类药物耐受患者参加这项研究。从血液样本中分离外周血单核细胞和血小板，并在体外用 SMX-HA 进行细胞毒性、ROS 和羰基蛋白形成、脂质过氧化和 GSH（谷胱甘肽）含量分析。当用 SMX-HA 进行挑战时，来自磺胺类 HS 患者的细胞表现出明显（P≤0.05）更高的细胞死亡、ROS 和羰基蛋白形成以及脂质过氧化。此外，PBMC 中的细胞死亡与 ROS 水平之间存在高度相关性。磺胺类 HS 患者外周血单个核细胞中的 GSH 也耗竭，GSH/GSSG 比值较低。形成的 ROS 量与细胞内 GSH 含量呈负相关。数据表明氧化应激在 SMX 反应性代谢物的体外细胞毒性中起主要作用，并表明磺胺类 HS 患者的细胞对体外挑战的易感性增加。
