A novel mouse model for phenytoin-induced liver injury: involvement of immune-related factors and P450-mediated metabolism.
A novel mouse model for phenytoin-induced liver injury: involvement of immune-related factors and P450-mediated metabolism.
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DOI：
10.1093/toxsci/kft184
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
E. Sasaki;K. Matsuo;A. Iida;K. Tsuneyama;T. Fukami;M. Nakajima;T. Yokoi
中科院分区：
文献类型：
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作者：
E. Sasaki;K. Matsuo;A. Iida;K. Tsuneyama;T. Fukami;M. Nakajima;T. Yokoi
药物性肝损伤是药物开发和临床药物治疗的重要问题;然而，在大多数情况下，由于缺乏合适的动物模型和未知的作用机制，难以预测或预防这些反应。苯妥英钠（DPH）是一种抗惊厥药物，广泛用于治疗癫痫。一些服用DPH的患者会出现以肝坏死为特征的药物性肝损伤症状。DPH诱导的肝损伤发生在1/1000或1/10000患者中。临床上，75%的肝损伤患者会出现发烧，63%的患者会出现皮疹。本研究建立了DPH诱导的小鼠肝损伤模型，并分析了免疫相关或炎症相关因素以及代谢活化对DPH肝毒性的影响机制。雌性C57 BL/6小鼠被给予DPH与L-丁硫氨酸-S，R-亚砜亚胺的组合5天。然后，血浆丙氨酸氨基转移酶（ALT）水平升高，组织学评价期间观察到肝脏病变，肝脏谷胱甘肽水平显着降低，氧化应激标志物水平显着升高。细胞色素P450依赖性氧化代谢的抑制显著抑制了血浆ALT水平的升高和肝脏谷胱甘肽的耗竭。在先天免疫因子中，肝脏NACHT、LRR、含pyrin结构域蛋白3、白细胞介素1β和损伤相关分子模式的mRNA水平显著升高。前列腺素E治疗可减轻BPH引起的肝损害。总之，细胞色素P450依赖的代谢活化，然后刺激先天免疫反应参与了DPH诱导的肝损伤。
Drug-induced liver injury is an important issue for drug development and clinical drug therapy; however, in most cases, it is difficult to predict or prevent these reactions due to a lack of suitable animal models and the unknown mechanisms of action. Phenytoin (DPH) is an anticonvulsant drug that is widely used for the treatment of epilepsy. Some patients who are administered DPH will suffer symptoms of drug-induced liver injury characterized by hepatic necrosis. DPH-induced liver injury occurs in 1 in 1000 or 1 in 10 000 patients. Clinically, 75% of patients who develop liver injury develop a fever and 63% develop a rash. In this study, we established a mouse model for DPH-induced liver injury and analyzed the mechanisms for hepatotoxicity in the presence of immune-related or inflammation-related factors and metabolic activation. Female C57BL/6 mice were administered DPH for 5 days in combination with L-buthionine-S,R-sulfoximine. Then, the plasma alanine aminotransferase (ALT) levels were increased, hepatic lesions were observed during the histological evaluations, the hepatic glutathione levels were significantly reduced, and the oxidative stress marker levels were significantly increased. The inhibition of cytochrome P450-dependent oxidative metabolism significantly suppressed the elevated plasma ALT levels and depleted hepatic glutathione. Among the innate immune factors, the hepatic mRNA levels of NACHT, LRR, pyrin domain-containing protein 3, interleukin-1β, and damage-associated molecular patterns were significantly increased. Prostaglandin E₁ treatment ameliorated the hepatic injury caused by DPH. In conclusion, cytochrome P450-dependent metabolic activation followed by the stimulation of the innate immune responses is involved in DPH-induced liver injury.