Development of an In Vitro Model to Predict Idiosyncratic Drug Induced Liver Injury
Rice, Gabriel P.
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Idiosyncratic drug induced liver injury (IDILI) is a major concern within the pharmaceutical and clinical community due to its unpredictability and harmful effects. Current screening methods for classifying drugs that have IDILI liability are not effective. Immune responses are thought to play an underlying role. Maiuri et al. have shown that several IDILI associated drugs interacted synergistically with tumor necrosis factor a (TNF) in HepG2 cells, however the response was more apparent with drugs that cause hepatocellular injury rather than cholestatic injury. For example, flutamide is known to cause cholestatic IDILI, but did not produce a hepatotoxic synergy with TNF in HepG2 cells. Flutamide is also known to inhibit transport of bile acids. It has been suggested that cholestatic related liver injury involves bile acids, and that flutamide didn’t cause hepatotoxicity because HepG2 cells do not have important bile acid transporters. It was hypothesized that an accumulation of intrahepatic bile acids caused by flutamide would induce ER-stress, which when combined with TNF would cause a sustained activation of c-Jun N-terminal kinase (JNK), leading to hepatotoxicity. Primary hepatocytes were exposed to various concentrations of flutamide, TNF, and glycochenodeoxycholic acid (GCDA) or chenodeoxycholic acid (CDCA). After 72 hrs of exposure, flutamide in the presence of TNF and GCDA caused a synergistic toxicity. These findings support the hypotheses that actions of flutamide cause a intrahepatic accumulation of bile acids, which in combination with TNF, cause toxicity.