Cellular imaging predictions of clinical drug-induced liver injury.
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.
Xu
Jinghai J
JJ
Predictive Toxicology, Pfizer Research Technology Center, Pfizer Global Research and Development, Cambridge, Massachussetts 01239, USA.
Henstock
Peter V
PV
Dunn
Margaret C
MC
Smith
Arthur R
AR
Chabot
Jeffrey R
JR
de Graaf
David
D
D002478:Cells, Cultured; D019992:Databases as Topic; D005189:False Positive Reactions; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008930:Mitochondria, Liver / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000145:classification; D010599:Pharmacokinetics; D012372:ROC Curve
D004364:Pharmaceutical Preparations