Many drugs have the potential to cause drug-induced liver injury (DILI); however, underlying mechanisms are diverse. The concept of adverse outcome pathways (AOPs) has become instrumental for risk assessment of drug class effects. We report AOPs specific for immune-mediated and drug hypersensitivity/allergic hepatitis by considering genomic, histo- and clinical pathology data of mice and dogs treated with diclofenac. The findings are relevant for other NSAIDs and drugs undergoing iminoquinone and quinone reactive metabolite formation. We define reactive metabolites catalyzed by CYP monooxygenase and myeloperoxidases of neutrophils and Kupffer cells as well as acyl glucuronides produced by uridine diphosphoglucuronosyl transferase as molecular initiating events (MIE). The reactive metabolites bind to proteins and act as neo-antigen and involve antigen-presenting cells to elicit B- and T-cell responses. Given the diverse immune systems between mice and dogs, six different key events (KEs) at the cellular and up to four KEs at the organ level are defined with mechanistic plausibility for the onset and progression of liver inflammation. With mice, cellular stress response, interferon gamma-, adipocytokine- and chemokine signaling provided a rationale for the AOP of immune-mediated hepatitis. With dogs, an erroneous programming of the innate and adaptive immune response resulted in mast cell activation; their infiltration into liver parenchyma and the shift to M2-polarized Kupffer cells signify allergic hepatitis and the occurrence of granulomas of the liver. Taken together, diclofenac induces divergent immune responses among two important preclinical animal species, and the injury pattern seen among clinical cases confirms the relevance of the developed AOP for immune-mediated hepatitis.

译文

:许多药物都有可能引起药物性肝损伤(DILI);但是,潜在的机制是多种多样的。不良结局途径(AOP)的概念已成为评估药物类别影响的工具。通过考虑用双氯芬酸治疗的小鼠和狗的基因组,组织学和临床病理数据,我们报告了特异性针对免疫介导的和药物超敏性/过敏性肝炎的AOP。该发现与其他非甾体抗炎药和正在经历亚氨基醌和醌反应性代谢产物形成的药物有关。我们定义了由CYP单加氧酶和嗜中性粒细胞和Kupffer细胞的髓过氧化物酶以及尿苷二磷酸葡萄糖醛糖苷转移酶产生的酰基葡萄糖醛酸苷作为分子引发事件(MIE)催化的反应性代谢产物。反应性代谢物与蛋白质结合并充当新抗原,并涉及抗原呈递细胞以引发B细胞和T细胞反应。考虑到小鼠和狗之间的免疫系统各不相同,在细胞水平上定义了六个不同的关键事件(KE),在器官水平上定义了多达四个KE,并且对于肝脏炎症的发生和发展具有机理上的合理性。对于小鼠,细胞应激反应,干扰素γ,脂肪细胞因子和趋化因子信号传导为免疫介导的肝炎的AOP提供了理论依据。对于狗,先天和适应性免疫反应的错误编程导致肥大细胞激活。它们浸润到肝实质中,并转移到M2极化的Kupffer细胞,这表示过敏性肝炎和肝肉芽肿的发生。综上所述,双氯芬酸在两种重要的临床前动物物种之间诱导不同的免疫反应,临床病例中观察到的损伤模式证实了已开发的AOP与免疫介导的肝炎的相关性。

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