Dansette P M, Bonierbale E, Minoletti C, Beaune P H, Pessayre D, Mansuy D
Université Ren Descartes, CNRS URA 400, Paris, France.
Eur J Drug Metab Pharmacokinet. 1998 Oct-Dec;23(4):443-51. doi: 10.1007/BF03189993.
Immune-related drug responses are one of the most common sources of idiosyncratic toxicity. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independence; c) typical immune system manifestations such as fever, eosinophilia; d) delay between the initiation of treatment and onset of the disease; e) a shortened delay upon rechallenge; and f) occasional presence of autoantibodies in the serum of patients. Such signs have been found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms have been postulated: 1) the drug is first metabolized into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, might trigger an immune response characterized by 3) the production of antibodies recognizing both the native and/or the modified protein; 4) rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.
免疫相关药物反应是特异质性毒性最常见的来源之一。许多器官可能是此类反应的靶器官；然而，本综述主要集中于肝脏。药物性肝炎通常分为两类：一类是急性肝炎，药物或其代谢产物破坏细胞中的关键靶点；另一类是免疫过敏性肝炎，药物引发针对肝脏的不良免疫反应。其临床特征为：a）发生率低；b）与剂量无关；c）有典型的免疫系统表现，如发热、嗜酸性粒细胞增多；d）治疗开始与疾病发作之间有延迟；e）再次用药时延迟缩短；f）患者血清中偶尔出现自身抗体。在由氟烷、替尼酸、肼屈嗪和抗惊厥药等药物引发的肝炎病例中已发现这些迹象。将以它们为例来说明在确定该疾病发病机制方面取得的最新进展。已提出以下机制：1）药物首先代谢为一种反应性代谢产物，该代谢产物与产生它的酶结合；2）这产生一种新抗原，一旦呈递给免疫系统，可能引发免疫反应，其特征为3）产生识别天然和/或修饰蛋白的抗体；4）再次用药导致新抗原产生增加，在这种情况下抗体的存在可能诱导细胞溶解。毒性与新抗原的性质和数量以及个体免疫系统等其他因素有关。应努力更好地理解这类疾病的确切发病机制，从而识别有风险的药物；以及将它们引入免疫系统所需的新抗原过程。在这方面动物模型会很有用。
