Mechanistic Assays - Inflammation-mediated Toxicity
Detect potential indirect drug-induced hepatotoxicity by inducing an inflammatory response
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.
Toxicity of Trovafloxacin in presence of inflammation. 3D InSight™ Human Liver Microtissues (co-culture model with human Kupffer cells), were treated with Trovafloxacin and the structurally related compound Levofloxacin in presence or absence of LPS. Synergistic toxicity of inflammation with a compound was only observed for Trovafloxacin, but not with the clinically safe drug Levofloxacin. Figure adapted from (3).
- Roth et al, Journal of Pharmacology and Experimental Therapeutics (2017)
- Beggs et al, Toxicological Sciences (2014)
- Messner et al, Archives of Toxicology (2013)