Inflammation-mediated Toxicity

Idiosyncratic drug-induced liver injury continues to be a serious human health problem. Several hypotheses involving the inflammatory system’s inability to adapt to stress and multiple concurrent factors have been proposed (1). Idiosyncratic DILI accounts for 17% of all cases of acute liver failure (2). Trovafloxacin, which causes idiosyncratic DILI in humans, is often used as a model compound. Recently, it was shown that Trovafloxacin interacts with TNF to cause hepatocellular death (2). 3D InSight™ Liver Microtissues, co-culture models that combine inflammatory cells, such as Kupffer cells, with primary human hepatocytes, enable testing of potential idiosyncratic, inflammation-mediated toxicity, as the direct interaction of cell-types enables direct cytokine signaling from primary macrophages to hepatocytes. For example, it has been demonstrated that the co-exposure of Trovafloxacin with Lipopolysaccharides (LPS) allows detection of the idiosyncratic toxicity of this drug in 3D InSight™ Human Liver Microtissues (3).

• Use an advanced 3D co-culture model with inflammatory Kupffer cells and hepatocytes that captures direct cytokine signaling for hepatocyte acute-phase protein induction.
• Capture enhanced toxicity of Trovafloxacin, a model compound for idiosyncratic toxicity, following induction of an inflammatory state with LPS treatment.
• Ensure mechanistic accuracy with an in vitro model that displays high specificity, detecting Trovafloxacin toxicity only in co-culture (not in hepatocyte monocultures). Furthermore, Trovafloxacin's structurally-related, but non-toxic analog Levofloxacin was confirmed safe in this model.