Popovic M, Shenton J M, Chen J, Baban A, Tharmanathan T, Mannargudi B, Abdulla D, Uetrecht J P
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada.
Handb Exp Pharmacol. 2010(196):437-51. doi: 10.1007/978-3-642-00663-0_15.
Treatment of HIV-1 infections with nevirapine is associated with skin and liver toxicity. These two organ toxicities range from mild to severe, in rare cases resulting in life-threatening liver failure or toxic epidermal necrolysis. The study of the mechanistic steps leading to nevirapine-induced skin rash has been facilitated by the discovery of an animal model in which nevirapine causes a skin rash in rats that closely mimics the rash reported in patients. The similarity in characteristics of the rash between humans and rats strongly suggests that the basic mechanism is the same in both. The rash is clearly immune-mediated in rats, and partial depletion of CD4(+) T cells, but not CD8(+) T cells, is protective. We have demonstrated that the rash is related to the 12-hydroxylation of nevirapine rather than to the parent drug. This is presumably because the 12-hydroxy metabolite can be converted to a reactive quinone methide in skin, but that remains to be demonstrated. Although the rash is clearly related to the 12-hydroxy metabolite rather than the parent drug, cells from rechallenged animals respond ex vivo to the parent drug by producing cytokines such as interferon-gamma with little response to the 12-hydroxy metabolite, even when the rash was induced by treatment with the metabolite rather than the parent drug. This indicates that the response of T cells in vitro cannot be used to determine what caused an immune response. We are now studying the detailed steps by which the 12-hydroxy metabolite induces an immune response and skin rash. This animal model provides a unique tool to study the mechanistic details of an idiosyncratic drug reaction; however, it is likely that there are significant differences in the mechanisms of different idiosyncratic drug reactions, and therefore the results of these studies cannot safely be generalized to all idiosyncratic drug reactions.
使用奈韦拉平治疗HIV-1感染与皮肤和肝脏毒性相关。这两种器官毒性从轻度到重度不等，在罕见情况下会导致危及生命的肝衰竭或中毒性表皮坏死松解症。一种动物模型的发现促进了对导致奈韦拉平诱发皮疹的机制步骤的研究，在该模型中，奈韦拉平会在大鼠身上引发皮疹，与患者报告的皮疹极为相似。人类和大鼠皮疹特征的相似性强烈表明两者的基本机制相同。在大鼠中，皮疹显然是免疫介导的，CD4(+) T细胞部分耗竭具有保护作用，而CD8(+) T细胞耗竭则不然。我们已经证明皮疹与奈韦拉平的12-羟基化有关，而非与母体药物有关。据推测，这是因为12-羟基代谢物可在皮肤中转化为反应性醌甲基化物，但这一点仍有待证实。尽管皮疹显然与12-羟基代谢物而非母体药物有关，但再次接受攻击的动物的细胞在体外对母体药物产生细胞因子（如干扰素-γ）有反应，而对12-羟基代谢物反应甚微，即使皮疹是由代谢物而非母体药物治疗诱发的。这表明体外T细胞的反应不能用于确定引发免疫反应的原因。我们目前正在研究12-羟基代谢物诱发免疫反应和皮疹的详细步骤。这种动物模型为研究特异质药物反应的机制细节提供了独特的工具；然而，不同特异质药物反应的机制可能存在显著差异，因此这些研究结果不能安全地推广到所有特异质药物反应。
