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Int J Mol Sci. 2017 Mar 7;18(3). pii: E574. doi: 10.3390/ijms18030574.

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices.

Author information

1
Human Translational Models LLC, P.O. Box 4593, Irvine, CA 92612, USA. aemvickers@me.com.
2
Inova Translational Medicine Institute, Inova Hospital, Fairfax, VA 22031, USA.
3
Vitron, Inc., Tucson, AZ 85747, USA.

Abstract

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.

KEYWORDS:

drug injury; human liver slices

PMID:
28272341
PMCID:
PMC5372590
DOI:
10.3390/ijms18030574
[Indexed for MEDLINE]
Free PMC Article

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