Inflammation-mediated Toxicity | InSphero

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.

Example Data

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).

References

  1. Roth et al, Journal of Pharmacology and Experimental Therapeutics (2017)
  2. Beggs et al, Toxicological Sciences (2014)
  3. Messner et al, Archives of Toxicology (2013)

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