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

Benjamin D. Cosgrove, Bracken M. King, Maya A. Hasan, Leonidas G. Alexopoulos, Paraskevi A. Farazi, Bart S. Hendriks, Linda G. Griffith, Peter K. Sorger, Bruce Tidor, Jinghai J. Xu, Douglas A. Lauffenburger

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)317-330
Number of pages14
JournalToxicology and Applied Pharmacology
Volume237
Issue number3
DOIs
StatePublished - Jun 15 2009

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Cytokines
Inflammation
Pharmaceutical Preparations
Assays
nimesulide
Interleukin-1
Hepatocytes
Screening
In Vitro Techniques
Throughput
Famotidine
Buspirone
Levofloxacin
Ranitidine
Clarithromycin
Hep G2 Cells
Aspirin
Rats
Rodentia
Interleukin-6

Keywords

  • Adverse drug reactions
  • Drug-induced liver injury
  • Information theory
  • Partial least-squares modeling
  • Pre-clinical assays

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. / Cosgrove, Benjamin D.; King, Bracken M.; Hasan, Maya A.; Alexopoulos, Leonidas G.; Farazi, Paraskevi A.; Hendriks, Bart S.; Griffith, Linda G.; Sorger, Peter K.; Tidor, Bruce; Xu, Jinghai J.; Lauffenburger, Douglas A.

In: Toxicology and Applied Pharmacology, Vol. 237, No. 3, 15.06.2009, p. 317-330.

Research output: Contribution to journalArticle

Cosgrove, BD, King, BM, Hasan, MA, Alexopoulos, LG, Farazi, PA, Hendriks, BS, Griffith, LG, Sorger, PK, Tidor, B, Xu, JJ & Lauffenburger, DA 2009, 'Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity', Toxicology and Applied Pharmacology, vol. 237, no. 3, pp. 317-330. https://doi.org/10.1016/j.taap.2009.04.002
Cosgrove, Benjamin D. ; King, Bracken M. ; Hasan, Maya A. ; Alexopoulos, Leonidas G. ; Farazi, Paraskevi A. ; Hendriks, Bart S. ; Griffith, Linda G. ; Sorger, Peter K. ; Tidor, Bruce ; Xu, Jinghai J. ; Lauffenburger, Douglas A. / Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. In: Toxicology and Applied Pharmacology. 2009 ; Vol. 237, No. 3. pp. 317-330.
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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.",
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