Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Drug Metab Pharmacokinet. 2011;26(1):47-59. doi: 10.2133/dmpk.dmpk-10-rv-085. Epub 2010 Nov 12.
There is strong evidence that most idiosyncratic drug reactions (IDRs) are immune-mediated and are caused by reactive metabolites of a drug rather than by the drug itself. Several hypotheses have been proposed by which a drug could induce an immune response. The major hypotheses are the hapten hypothesis and the danger hypothesis; however, the characteristics and spectrum of IDRs are different with different drugs, and this likely reflects mechanistic differences; therefore, no one hypothesis is likely to explain all IDRs. Some IDRs appear to involve epigenetic effects, direct activation of antigen-presenting cells, or disturbing the normal balance of the immune system. It has been suggested that many cases of idiosyncratic liver injury are not immune-mediated, and other mechanisms such as mitochondrial injury may be involved. It is essential that any hypothesis be consistent with the clinical characteristics of the IDR. Although the characteristics of most idiosyncratic liver injury do not suggest that mitochondria are the major target, it is quite possible that milder mitochondrial injury could stimulate an immune-mediated reaction. The observation that IDRs can vary widely among different drugs and different patients is most easily explained by an immune mechanism in which the target of the immune response is different.
有强有力的证据表明，大多数特异质药物反应（IDR）是免疫介导的，是由药物的反应性代谢物引起的，而不是药物本身。已经提出了几个假设，通过这些假设药物可以诱导免疫反应。主要的假设是半抗原假说和危险假说；然而，不同药物的 IDR 的特征和谱是不同的，这可能反映了机制上的差异；因此，没有一个假设可以解释所有的 IDR。一些 IDR 似乎涉及表观遗传效应、抗原呈递细胞的直接激活，或扰乱免疫系统的正常平衡。有人认为，许多特异质肝损伤的病例不是免疫介导的，可能涉及其他机制，如线粒体损伤。任何假设都必须与 IDR 的临床特征一致，这一点至关重要。虽然大多数特异质肝损伤的特征并不表明线粒体是主要靶点，但轻微的线粒体损伤很可能刺激免疫介导的反应。在不同药物和不同患者之间 IDR 变化范围很广的现象，最容易用免疫机制来解释，在这种免疫机制中，免疫反应的靶标是不同的。
