Meekins C V, Sullivan T J, Gruchalla R S
University of Texas Southwestern Medical Center, Dallas.
J Allergy Clin Immunol. 1994 Dec;94(6 Pt 1):1017-24. doi: 10.1016/0091-6749(94)90120-1.
Sulfonamides undergo oxidative metabolism to yield reactive metabolites that haptenate proteins readily. Although it has been shown that sulfonamide metabolites bind covalently to murine microsomes, sulfonamide-conjugated serum proteins have not been analyzed in the peripheral blood of treated individuals.
We hypothesized that during treatment with sulfamethoxazole, intracellular proteins are haptenated by drug metabolites, and some of these are destined for secretion into the serum.
Using antibodies specific for sulfamethoxazole and an alkaline phosphatase immunoblotting technique, we attempted to demonstrate the presence of sulfamethoxazole-substituted proteins in the serum of individuals during a course of treatment.
Five days into therapy, serum protein haptenation by sulfamethoxazole was demonstrated in two of the three individuals studied. In addition, Western blot analysis revealed that haptenation is not indiscriminate, but highly selective. A single 30 kd protein is the target of haptenation in all instances. A kinetic analysis revealed that substituted proteins can be detected early, within hours of administration. Moreover, haptenated proteins remain detectable in the serum 48 hours after discontinuation of the drug.
The results presented here constitute the first direct evidence that sulfonamides, on being metabolized, covalently haptenate human serum proteins during a course of therapy.
磺胺类药物经氧化代谢产生易于与蛋白质形成半抗原的反应性代谢产物。尽管已表明磺胺类药物代谢产物可与小鼠微粒体共价结合，但尚未对接受治疗个体外周血中的磺胺类药物结合血清蛋白进行分析。
我们推测在使用磺胺甲恶唑治疗期间，细胞内蛋白质会被药物代谢产物半抗原化，其中一些会分泌到血清中。
我们使用针对磺胺甲恶唑的特异性抗体和碱性磷酸酶免疫印迹技术，试图证明在治疗过程中个体血清中存在磺胺甲恶唑取代的蛋白质。
在研究的三名个体中，有两名在治疗五天后显示血清蛋白被磺胺甲恶唑半抗原化。此外，蛋白质印迹分析表明半抗原化并非随机发生，而是具有高度选择性。在所有情况下，单一的30kd蛋白都是半抗原化的靶点。动力学分析显示，给药后数小时内即可早期检测到被取代的蛋白质。此外，停药48小时后血清中仍可检测到半抗原化蛋白。
此处给出的结果构成了首个直接证据，表明磺胺类药物在代谢过程中，在治疗过程中会与人血清蛋白共价结合形成半抗原。
