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ToxSci Advance Access originally published online on June 3, 2008
Toxicological Sciences 2008 105(1):97-105; doi:10.1093/toxsci/kfn109
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Cellular Imaging Predictions of Clinical Drug-Induced Liver Injury

Jinghai J. Xu*,{dagger},1, Peter V. Henstock{ddagger}, Margaret C. Dunn*,{dagger}, Arthur R. Smith*,{dagger}, Jeffrey R. Chabot{dagger} and David de Graaf{dagger},2

* Predictive Toxicology, Pfizer Research Technology Center, Pfizer Global Research and Development, Cambridge, Massachussetts 01239 {dagger} Systems Biology, Pfizer Research Technology Center, Pfizer Global Research and Development, Cambridge, Massachussetts 01239 {ddagger} Target & Mechanism Informatics, Pfizer Research Technology Center, Pfizer Global Research and Development, Cambridge, Massachussetts 01239

2 To whom correspondence should be addressed at Systems Biology, Pfizer Research Technology Center, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 01239. E-mail: david.degraaf{at}pfizer.com

Received April 2, 2008; accepted May 22, 2008


  Abstract

Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction. When applied to over 300 drugs and chemicals including many that caused rare and idiosyncratic liver toxicity in humans, our testing strategy has a true-positive rate of 50–60% and an exceptionally low false-positive rate of 0–5%. These in vitro predictions can augment the performance of the combined traditional preclinical animal tests by identifying idiosyncratic human hepatotoxicants such as nimesulide, telithromycin, nefazodone, troglitazone, tetracycline, sulindac, zileuton, labetalol, diclofenac, chlorzoxazone, dantrolene, and many others. Our findings provide insight to key DILI mechanisms, and suggest a new approach in hepatotoxicity testing of pharmaceuticals.

Key Words: liver injury; idiosyncratic hepatotoxicity; hepatitis; mechanism of organ toxicity; in vitro in vivo correlations; pharmacokinetic scaling; hepatotoxicity testing.

1 Current address: Department of Automated Biotechnology, Merck & Co., 140 Wissahickon Ave., North Wales, PA 19454.


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