Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, minami-ku, Fukuoka 815-8511, Japan.
Int Immunopharmacol. 2012 Apr;12(4):694-700. doi: 10.1016/j.intimp.2012.01.017. Epub 2012 Feb 13.
Drug induced allergies are believed to be induced by conjugates consisting of biological macromolecules and active metabolites. The present study investigated whether guinea pig glutathione S-transferase (gpGST), a protein that binds with sulfanilamide (SA) and sulfamethoxazole (SMX), could be detected in the liver cytosol fraction of guinea pigs that intraperitoneally received SA or SMX, and whether gpGST is a carrier protein. We synthesized three nitroso compounds, i.e., 4-nitroso-sulfanilamide (SA-NO), 4-nitrososulfamethoxazole (SMX-NO) and fluorescent-labeled nitroso compound (DNSBA-NO), and examined binding quantities of nitroso compounds to gpGST purified from untreated female guinea pigs. Furthermore, the concentrations of IgG in serum antibody for nitroso compounds were estimated using ELISA. When guinea pigs were sensitized using the three nitroso compounds, the dose dependent skin reactions were confirmed with each compound. In addition, sensitized guinea pigs using each nitroso compound showed positive skin reactions at an elicitation test performed using gpGST alone. The results confirmed synthesis of antibody against gpGST due to hapten sensitization. Therefore, when a nitroso compound binds with gpGST in the body of guinea pigs, nitroso-gpGST acts as a neoantigen, which induces synthesis of autoantibody. Thus, gpGST appears to be one of the carrier proteins that induce sulfa drug-induced allergies. Immunization of guinea pigs with active metabolite of drugs may give information for predicting the occurrence of delayed type hypersensitivity in human.
药物诱导的过敏反应被认为是由生物大分子和活性代谢物组成的缀合物引起的。本研究探讨了是否可以在腹腔内给予磺胺（SA）和磺胺甲恶唑（SMX）的豚鼠肝胞质部分中检测到与磺胺结合的豚鼠谷胱甘肽 S-转移酶（gpGST），以及 gpGST 是否是载体蛋白。我们合成了三种亚硝基化合物，即 4-亚硝基磺胺（SA-NO），4-亚硝基磺胺甲恶唑（SMX-NO）和荧光标记的亚硝基化合物（DNSBA-NO），并检查了未处理的雌性豚鼠纯化的 gpGST 与亚硝基化合物的结合量。此外，使用 ELISA 估计了血清抗体中针对亚硝基化合物的 IgG 浓度。当使用三种亚硝基化合物对豚鼠进行致敏时，用每种化合物证实了剂量依赖性的皮肤反应。此外，用每种亚硝基化合物致敏的豚鼠在单独使用 gpGST 进行的激发试验中表现出阳性皮肤反应。结果证实了由于半抗原致敏而产生针对 gpGST 的抗体的合成。因此，当体内的亚硝基化合物与 gpGST 结合时，亚硝基-gpGST 充当新抗原，诱导自身抗体的合成。因此，gpGST 似乎是引起磺胺类药物过敏的载体蛋白之一。用药物的活性代谢物免疫豚鼠可能会提供有关预测人类迟发性超敏反应发生的信息。
