OpenTox Euro 2019 talk: An adverse outcome pathway for diclofenac induced immune mediated and allergic hepatitis

Many drugs have the potential to cause drug induced liver injury; however underlying mechanisms are diverse. The adverse outcome pathways (AOPs) concept is a conceptual framework with the potential to improve an assessment of adverse drug reactions (ADRs). 

We developed AOPs specific for diclofenac induced immune mediated and allergic hepatitis based on the comprehensive data obtained from mice and dog repeated dose studies. The reactive metabolites catalysed by CYP monooxygenase and myeloperoxidases of Kupffer cells and neutrophils are defined as molecular initiating events (MIE). The reactive metabolites covalently bind to the hepatic proteins and function as neo-antigen and involve antigen presenting cells to elicit B-and T-cell responses. Given the different immune system between mice and dogs key events (KE) at the cellular and organ level are defined the onset and progression of liver inflammation. With mice, cellular stress response and inflammatory signaling pathways provide a rational for an AOP of immune-mediated hepatitis. With dogs, an erroneous programming of the innate and adaptive immune response results allergic hepatitis. Taken together, diclofenac induces divergent immune-response among two important animal models and the injury pattern seen among clinical cases strongly supports the relevance of the developed AOP for immune-mediated hepatitis.