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Evaluation of multiple mechanism-based toxicity endpoints in primary cultured human hepatocytes for the identification of drugs with clinical hepatotoxicity: Results from 152 marketed drugs with known liver injury profiles.

Publication ,  Journal Article
Zhang, J; Doshi, U; Suzuki, A; Chang, C-W; Borlak, J; Li, AP; Tong, W
Published in: Chem Biol Interact
August 5, 2016

We report here the results of a collaborative research program to develop a robust and reliable in vitro system to allow an accurate definition of the drug-induced liver injury (DILI) potential of new drug entities during drug development. The in vitro hepatotoxic potential of 152 drugs with known DILI profiles were evaluated in primary cultured human hepatocytes with four mechanistically-relevant endpoints: cellular ATP depletion, reactive oxygen species (ROS), glutathione (GSH) depletion, and caspase activation for apoptosis. The drugs, 80 in the testing set and 72 in the validation set, were classified based on serious clinical/regulatory outcomes as defined by reported acute liver failure, black-box warning, and/or withdrawal. The drugs were further sub-categorized for dominant types of liver injury. Logistic regression models were performed to calculate the area under the receiver operating characteristics curve (AUROC) and to evaluate the prediction potential of the selected endpoints for serious clinical/regulatory outcomes. The ROS/ATP ratio was found to yield an excellent AUROC in both the testing (0.8989, P < 0.0001) and validation set (0.8545, P < 0.0001), and was found to distinguish drugs associated with severe from non-severe DILI cases (p < 0.0001). The results suggest that evaluation of drugs in primary human hepatocytes using the ROS/ATP ratio endpoint may aid the definition of their potential to cause severe DILI.

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Published In

Chem Biol Interact

DOI

EISSN

1872-7786

Publication Date

August 5, 2016

Volume

255

Start / End Page

3 / 11

Location

Ireland

Related Subject Headings

  • Young Adult
  • Toxicology
  • Reactive Oxygen Species
  • Pharmaceutical Preparations
  • Middle Aged
  • Male
  • Liver
  • Humans
  • Hepatocytes
  • Glutathione
 

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Zhang, J., Doshi, U., Suzuki, A., Chang, C.-W., Borlak, J., Li, A. P., & Tong, W. (2016). Evaluation of multiple mechanism-based toxicity endpoints in primary cultured human hepatocytes for the identification of drugs with clinical hepatotoxicity: Results from 152 marketed drugs with known liver injury profiles. Chem Biol Interact, 255, 3–11. https://doi.org/10.1016/j.cbi.2015.11.008
Zhang, Jie, Utkarsh Doshi, Ayako Suzuki, Ching-Wei Chang, Jürgen Borlak, Albert P. Li, and Weida Tong. “Evaluation of multiple mechanism-based toxicity endpoints in primary cultured human hepatocytes for the identification of drugs with clinical hepatotoxicity: Results from 152 marketed drugs with known liver injury profiles.Chem Biol Interact 255 (August 5, 2016): 3–11. https://doi.org/10.1016/j.cbi.2015.11.008.
Journal cover image

Published In

Chem Biol Interact

DOI

EISSN

1872-7786

Publication Date

August 5, 2016

Volume

255

Start / End Page

3 / 11

Location

Ireland

Related Subject Headings

  • Young Adult
  • Toxicology
  • Reactive Oxygen Species
  • Pharmaceutical Preparations
  • Middle Aged
  • Male
  • Liver
  • Humans
  • Hepatocytes
  • Glutathione