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Int. J. Mol. Sci. 2017, 18(3), 574;

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

Human Translational Models LLC, P.O. Box 4593, Irvine, CA 92612, USA
Inova Translational Medicine Institute, Inova Hospital, Fairfax, VA 22031, USA
Vitron, Inc., Tucson, AZ 85747, USA
Author to whom correspondence should be addressed.
Academic Editor: Satohiro Masuda
Received: 31 January 2017 / Revised: 22 February 2017 / Accepted: 28 February 2017 / Published: 7 March 2017
(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)
Full-Text   |   PDF [4161 KB, uploaded 7 March 2017]   |  


Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 μM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM) and cyclosporin A (CSA, 10 μM), while GSH was affected more than ATP by methimazole (MMI, 500 μM), terbinafine (TBF, 100 μM), and carbamazepine (CBZ 100 μM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%–11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%–60%), APAP, CBZ (57%–56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%–43%), APAP and DCF (40%–38%), MMI, TBF and CSA (37%–35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects. View Full-Text
Keywords: human liver slices; drug injury human liver slices; drug injury

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Vickers, A.E.M.; Ulyanov, A.V.; Fisher, R.L. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices. Int. J. Mol. Sci. 2017, 18, 574.

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