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Ashley Maiuri - Thesis Proposal Defense
(Conferences / Seminars / Lectures)
An In Vitro Approach to Classify Drugs According to Their Potential to Cause Idiosyncratic Hepatotoxicity In Humans
HOST: Robert Roth
Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. Idiosyncratic drug-induced liver injury (IDILI), a subset of DILI, occurs in a small fraction of patients taking a drug and, although rare, can result in severe liver injury or death. Although the mechanisms of IDILI are not well understood, it has been hypothesized that an episode of inflammatory stress can render an individual susceptible to IDILI, and several animal models have been developed based on this hypothesis. These models demonstrate that drugs associated with IDILI increase and prolong lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF) release. The prolongation in TNF release is critical to the pathogenesis of liver injury. Enhanced release of TNF is associated with production of other inflammatory mediators such as interferon-gamma (IFN) and with activation of neutrophils that release toxic factors such as elastase. TNF, IFN, and elastase contribute to hepatocellular damage in IDILI models in vivo and in vitro. The goal of the proposed studies is to test the hypothesis that the capacity of drugs to 1) increase TNF production by macrophages in vitro and 2) sensitize hepatocytes to injurious effects of inflammatory mediators (TNF, IFN, and elastase) correlates with their potential to cause IDILI in humans. The data generated from the proposed studies will be used to develop a regression-based, supervised learning tool to determine which combination of events (i.e. a drug's ability to increase TNF release from macrophages in vitro and/or a drug's ability to sensitize hepatocytes to inflammatory mediators) most accurately classifies the IDILI potential of a drug. Knowledge generated from these studies will be useful in developing an approach that could be used during preclinical safety evaluation to identify drug candidates with the potential to cause IDILI.
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884-3553
