Stephens Camilla, Andrade Raúl J, Lucena M Isabel
Servicio de Farmacología Clínica and UGC de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Madrid, Spain.
Curr Opin Allergy Clin Immunol. 2014 Aug;14(4):286-92. doi: 10.1097/ACI.0000000000000070.
Idiosyncratic drug-induced liver injury (iDILI) is a relatively rare condition, but can have serious consequences for the individual patient, public health, regulatory agencies and the pharmaceutical industry. Despite increased awareness of iDILI, its underlying mechanism is still not fully understood. This review summarizes the current understanding of the molecular mechanism behind iDILI.
Genetic variations in drug metabolizing genes are in line with proposed mechanisms based on acetaminophen hepatotoxicity, whereby reactive metabolites covalently bind to cellular proteins and disturb the redox balance. In addition, immune-mediated effects have been reported for flucloxacillin hepatotoxicity, demonstrating both haptenization and direct binding between the drug and immune receptors.
Idiosyncratic DILI development is believed to be orchestrated by multiple events, such as reactive metabolite formations, oxidative stress and signalling pathway inductions, with the mitochondria taking centre stage. Evidence also points towards the immune system (innate and adaptive responses) as important components in iDILI. Interindividual differences in one or more of these events, due to genetic variations and environmental factors, are likely to contribute to the idiosyncratic nature of this condition and subsequently distinguish between patient susceptibility and tolerance.
特异质性药物性肝损伤（iDILI）是一种相对罕见的病症，但对个体患者、公共卫生、监管机构及制药行业都会产生严重后果。尽管对iDILI的认识有所提高，但其潜在机制仍未完全明确。本综述总结了目前对iDILI背后分子机制的理解。
药物代谢基因的遗传变异与基于对乙酰氨基酚肝毒性提出的机制相符，即反应性代谢产物与细胞蛋白共价结合并扰乱氧化还原平衡。此外，已有报道称氟氯西林肝毒性存在免疫介导效应，证明了药物与免疫受体之间的半抗原化和直接结合。
特异质性药物性肝损伤的发生被认为是由多种事件共同作用导致的，如反应性代谢产物形成、氧化应激和信号通路诱导，其中线粒体起着核心作用。证据还表明免疫系统（固有和适应性反应）是iDILI的重要组成部分。由于遗传变异和环境因素，这些事件中一个或多个的个体差异可能导致这种病症的特异质性，并进而区分患者的易感性和耐受性。
