Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity.
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.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Benjamin D
BD
Cosgrove
Bracken M
BM
King
Maya A
MA
Hasan
Leonidas G
LG
Alexopoulos
Paraskevi A
PA
Farazi
Bart S
BS
Hendriks
Linda G
LG
Griffith
Peter K
PK
Sorger
Bruce
B
Tidor
Jinghai J
JJ
Xu
Douglas A
DA
Lauffenburger
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D064420:Drug-Related Side Effects and Adverse Reactions; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D004364:Pharmaceutical Preparations / Q000145:classification / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D016207:Cytokines; D018836:Inflammation Mediators; D004364:Pharmaceutical Preparations