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Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.

Abstract：

:Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Proctor WR,Foster AJ,Vogt J,Summers C,Middleton B,Pilling MA,Shienson D,Kijanska M,Ströbel S,Kelm JM,Morgan P,Messner S,Williams D

doi

10.1007/s00204-017-2002-1

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

2849-2863

issue

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-017-2002-1

journal_volume

pub_type

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Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.