Department of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Osaka, Japan (R.K., Y.I., T.H.) and Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (J.U.)
Department of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Osaka, Japan (R.K., Y.I., T.H.) and Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (J.U.).
Drug Metab Dispos. 2019 Oct;47(10):1093-1096. doi: 10.1124/dmd.119.087981. Epub 2019 Jul 19.
Although the pathophysiology of carbamazepine-induced idiosyncratic or hypersensitivity reactions is unclear, they are presumed to be immune mediated, involving a complex interaction between drug metabolism and activation of the immune system. Cell stress can be caused by reactive metabolites, and this has the potential to release damage-associated molecular patterns (DAMPs), which are responsible for activation of the immune system. Idiosyncratic drug reactions occur mainly in the liver because of its role in drug metabolism and reactive metabolite formation. DAMPs can activate inflammasomes, which may be a common mechanism by which DAMPs lead to an immune response. In the present study, we investigated whether carbamazepine induces the release of DAMPs by using human hepatocarcinoma functional liver cell-4 (FLC-4) cells for bioactivation of carbamazepine. THP-1 cells, a human macrophage cell line, were used for detecting inflammasome activation. We found that increased caspase-1 activity and production of interleukin-1 by THP-1 cells were caused by the supernatant from the incubation of carbamazepine with FLC-4 cells. In the supernatant, heat shock protein 60 was significantly increased. In addition, 2-hydroxyiminostilbene, which is a metabolite of carbamazepine, activated inflammasomes. These results suggest that the reactive iminoquinone metabolite can directly activate inflammasomes or that stressed hepatocytes cause the release of DAMPs, which are responsible for inflammasome activation. The activation of inflammasomes may be an important step in the immune system activation by carbamazepine, which can lead to hypersensitivity reactions in some patients. SIGNIFICANCE STATEMENT: A metabolite of carbamazepine, 2-hydroxyiminostilbene itself, and the damage-associated molecular patterns released from hepatocytes incubated with carbamazepine activated inflammasomes. The activation of inflammasomes may be an important step in the immune system activation by carbamazepine, which can lead to hypersensitivity reactions in some patients.
尽管卡马西平引起的特异质或过敏反应的病理生理学尚不清楚，但据推测它们是免疫介导的，涉及药物代谢和免疫系统激活之间的复杂相互作用。活性代谢物可引起细胞应激，这有可能释放损伤相关分子模式（DAMPs），从而激活免疫系统。特异质药物反应主要发生在肝脏，因为肝脏在药物代谢和活性代谢物形成中起作用。DAMPs 可激活炎症小体，这可能是 DAMPs 导致免疫反应的共同机制。在本研究中，我们使用人肝癌功能细胞系 FLC-4 细胞对卡马西平进行生物活化，研究了卡马西平是否通过诱导 DAMPs 的释放来诱导炎症小体的激活。我们使用人巨噬细胞细胞系 THP-1 细胞来检测炎症小体的激活。我们发现，卡马西平与 FLC-4 细胞孵育后的上清液可引起 THP-1 细胞中 caspase-1 活性和白细胞介素-1 的产生增加。在该上清液中，热休克蛋白 60 显著增加。此外，卡马西平的代谢产物 2-羟基亚氨基苯并噻吩可激活炎症小体。这些结果表明，活性亚氨基醌代谢物可直接激活炎症小体，或者应激肝细胞导致 DAMPs 的释放，从而导致炎症小体的激活。炎症小体的激活可能是卡马西平激活免疫系统的重要步骤，这可能导致一些患者发生过敏反应。
卡马西平的一种代谢物，即 2-羟基亚氨基苯并噻吩本身，以及与卡马西平孵育的肝细胞释放的损伤相关分子模式，均可激活炎症小体。炎症小体的激活可能是卡马西平激活免疫系统的重要步骤，这可能导致一些患者发生过敏反应。
