TY - JOUR
T1 - Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity
AU - Cosgrove, Benjamin D.
AU - King, Bracken M.
AU - Hasan, Maya A.
AU - Alexopoulos, Leonidas G.
AU - Farazi, Paraskevi A.
AU - Hendriks, Bart S.
AU - Griffith, Linda G.
AU - Sorger, Peter K.
AU - Tidor, Bruce
AU - Xu, Jinghai J.
AU - Lauffenburger, Douglas A.
N1 - Funding Information:
The authors thank Arthur Smith and Margaret Dunn for assistance in conducting hepatotoxicity imaging assays and David de Graaf, Steve Tannenbaum, Ajit Dash, Walker Inman, Justin Pritchard, and Brian Joughin for helpful discussions. The authors acknowledge funding support from Pfizer Inc., the MIT Center for Cell Decision Processes (NIH grant P50-GM68762; D.A.L., P.K.S.), the MIT Biotechnology Process Engineering Center (L.G.G.), the MIT Center for Environmental Health Sciences (NIH grant U19ES011399; L.G.G.), a NIH/NIGMS Biotechnology Training Program Fellowship (NIH grant T32-GM008334; B.M.K.), and a Whitaker Foundation Graduate Fellowship (B.D.C.).
PY - 2009/6/15
Y1 - 2009/6/15
N2 - 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, IFNγ, IL-1α, 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-1α, 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.
AB - 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, IFNγ, IL-1α, 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-1α, 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.
KW - Adverse drug reactions
KW - Drug-induced liver injury
KW - Information theory
KW - Partial least-squares modeling
KW - Pre-clinical assays
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UR - http://www.scopus.com/inward/citedby.url?scp=67349272258&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2009.04.002
DO - 10.1016/j.taap.2009.04.002
M3 - Article
C2 - 19362101
AN - SCOPUS:67349272258
VL - 237
SP - 317
EP - 330
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 3
ER -