|
|||||
|
|
Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity |
|
| Authors: | Benjamin D. Cosgrove Bracken M. King Leonidas G. Alexopoulos Paraskevi A. Farazi Bart S. Hendriks Peter K. Sorger Bruce Tidor Jinghai J. Xu Douglas A. Lauffenburger |
| Affiliation: | a Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA b Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA c Cell Decision Processes Center, Massachusetts Institute of Technology, Cambridge, MA, USA d Biotechnology Process Engineering Center, Massachusetts Institute of Technology, Cambridge, MA, USA e Department of Systems Biology, Harvard Medical School, Boston, MA, USA f Pfizer Research Technology Center, Cambridge, MA, USA |
| Abstract: | 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. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |