Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 05/2009; 237(3):317-30. DOI: 10.1016/j.taap.2009.04.002
Source: PubMed


Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFN gamma, IL-1 alpha, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1 alpha, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.

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Available from: Bruce Tidor, Oct 07, 2015
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    • "The choice of Dicrocoelium as model for the present study is related to both the poor knowledge on its pathogenesis, very often masked by the frequent poliparasitism in ruminants, and to its high prevalence in sheep, goats, cattle and buffaloes of southern Italy (Cringoli et al., 2002; Maurelli et al., 2007; Rinaldi et al., 2009; Musella et al., 2011) and other regions of the Mediterranea area (Rojo-Vázquez et al., 2012). Specifically, in the present study we investigated the effects of somatic antigen of D. dendriticum on cell death mechanisms using two human hepatocyte cell lines, HepG2 and HuH7, representing an almost non-tumor (Cosgrove et al., 2009; Soldatow et al., 2013) and a tumor cell line, respectively. "
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    • "The potential utility of this new assay to screen metabolism-dependent hepatotoxins was evidenced by a set of bioactivable and nonbioactivable drugs (Tolosa et al. 2013). Similarly, several authors have proposed HCS-based assays to explore drug toxicity to a variety of liver cell models, including rodent hepatocytes (Chen et al. 2014; Cosgrove et al. 2009), hepatocytes cocultured with fibroblasts (Cole et al. 2014), HepaRG cells (Pernelle et al. 2011; Ranade et al. 2014), or HepG2 cells maintained in microfluidic devices (Ye et al. 2007) or combined with subcellular liver fractions (Garside et al. 2014; Westerink et al. 2011). These multiparametric strategies offer the possibility of detecting subtle toxicity-related changes with greater sensitivity than monoparametric cytotoxicity assays which detect overt toxicity (O'Brien et al. 2006; Tolosa et al. 2012b). "
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    • "The endotoxin, LPS, is released upon infection or from the gastrointestinal fauna and enters the blood stream and other tissues such as liver which also regulates the inflammatory and toxic responses towards LPS exposure [7], [22]. Inflammation-, cytokine- and endotoxin-associated idiosyncratic drug toxicities have also been reported to exhibit synergetic actions for the production of pro-inflammatory cytokines [23]–[25].We, therefore, have investigated the oxidative stress and associated metabolic complications of LPS and ASA on macrophages. Our previous study on acetaminophen showed increased mitochondrial and oxidative stress in J774.2 cells [12]. "
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