Uetrecht J P
Faculty of Pharmacy, University of Toronto, Canada.
Eur J Haematol Suppl. 1996;60:83-8. doi: 10.1111/j.1600-0609.1996.tb01651.x.
Central to most hypotheses of the mechanism of idiosyncratic drug-induced blood dyscrasias is the involvement of reactive metabolites. In view of the reactive nature of the majority of such metabolites, it is likely that they are formed by, or in close proximity to the blood cells affected. The major oxidative system of neutrophils generates hypochlorous acid. We have demonstrated that the drugs associated with the highest incidence of agranulocytosis are oxidized to reactive metabolites by hypochlorous acid and/or activated neutrophils. There are many mechanisms by which such reactive metabolites could induce agranulocytosis. In the case of aminopyrine-induced agranulocytosis, most cases appear to involve drug-dependent anti-neutrophil antibodies, and these are likely to be induced by cell membrane antigens modified by the reactive metabolite of aminopyrine. The target of agranulocytosis associated with many other drugs is usually neutrophil precursors and may involve cytotoxicity or a cell-mediated immune reaction induced by a reactive metabolite. In the case of aplastic anaemia, there is evidence in some cases for involvement of cytotoxic T cells, which could either be induced by metabolites generated by neutrophils, or more likely, by reactive metabolites generated by stem cells.
大多数关于特异质性药物诱导的血液系统异常机制的假说的核心是反应性代谢产物的参与。鉴于大多数此类代谢产物具有反应性，它们很可能是在受影响的血细胞内或其附近形成的。中性粒细胞的主要氧化系统会产生次氯酸。我们已经证明，与粒细胞缺乏症发生率最高相关的药物会被次氯酸和/或活化的中性粒细胞氧化为反应性代谢产物。这些反应性代谢产物可通过多种机制诱导粒细胞缺乏症。在氨基比林诱导的粒细胞缺乏症中，大多数病例似乎涉及药物依赖性抗中性粒细胞抗体，而这些抗体很可能是由氨基比林的反应性代谢产物修饰的细胞膜抗原诱导产生的。与许多其他药物相关的粒细胞缺乏症的靶标通常是中性粒细胞前体，可能涉及细胞毒性或由反应性代谢产物诱导的细胞介导的免疫反应。在再生障碍性贫血的情况下，某些病例有证据表明细胞毒性T细胞参与其中，这些细胞毒性T细胞要么由中性粒细胞产生的代谢产物诱导，要么更有可能由干细胞产生的反应性代谢产物诱导。
