Liu Zhang-Xu, Kaplowitz Neil
Department of Microbiology/Immunology, Keck School of Medicine, University of Southern California, Norris Cancer Center, Room 6318, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Clin Liver Dis. 2002 Aug;6(3):755-74. doi: 10.1016/s1089-3261(02)00025-9.
Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.
药物性免疫介导的肝损伤是一种针对肝脏的不良免疫反应，可导致具有肝炎、胆汁淤积或混合临床特征的疾病。氟烷、替尼酸、双肼屈嗪和抗惊厥药等药物引发肝炎反应，而氯丙嗪、红霉素、阿莫西林 - 克拉维酸、磺胺类药物和舒林酸等药物引发胆汁淤积或混合反应。药物代谢产生的不稳定代谢产物可能与细胞蛋白质或大分子结合，对肝细胞产生直接毒性作用。药物代谢过程中形成的蛋白质加合物可能被免疫系统识别为新抗原。免疫细胞激活随后可能产生自身抗体和细胞介导的免疫反应，进而损害肝细胞。细胞色素450是药物代谢中的主要氧化催化剂，它们可通过与自身产生的药物代谢产物共价结合形成新抗原。产生的自身抗体选择性地针对代谢母体药物的特定细胞色素同工酶。半抗原假说提出药物代谢产物可作为半抗原，通过与蛋白质共价结合来改变个体自身。危险假说提出免疫系统仅在抗原与危险信号（如细胞应激或细胞死亡）相关联时才对外来抗原作出反应。大多数与药物相关的临床明显不良肝脏事件是不可预测的，并且具有超敏反应特有的中间（1至8周）或长潜伏期（长达12个月）。当停用药物时，免疫介导的药物性肝病几乎总是消失或变得静止。如果继续使用甲基多巴、米诺环素和呋喃妥因，可产生类似自身免疫性肝炎的慢性肝炎。
