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. 2017 Mar 7;18(3):574.
doi: 10.3390/ijms18030574.

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

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Free PMC article

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

Alison E M Vickers et al. Int J Mol Sci. .
Free PMC article

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Time course of ATP and GSH levels (24–72 h) in human liver slices exposed to daily dosing of APAP (1 mM), DCF (1 mM), MMI (500 μM), TBF (100 μM), CBZ (100 μM), ETM (100 μM), DTL (10 μM), CSA (10 μM). Values were determined in 10 control slices or 6 treated slices/time-point/liver. Statistical significance, p < 0.05, is labeled (*) and related to the time-matched control value.
Figure 2
Figure 2
Human liver slice ATP and GSH mean levels are represented as percent of control (24, 48, 72 h) for the 3 individual livers to compare drug response across the livers.
Figure 3
Figure 3
Histograms of fold change and distribution of the 370 genes queried with the human specific Molecular Toxicology Pathway Finder PCR array. Each column corresponds to a drug and each row corresponds to the individual human livers (869, 870, 871). The global response to the drugs has the same distribution across the drugs, except for DCF and DTL in human liver 869 in which a greater number of genes were altered.
Figure 4
Figure 4
The gene categories for each drug are arranged to compare drug response of the 8 drugs used in this study. The percentage of genes represented by each category is based on the number of significant total gene changes for each drug, which is listed at the bottom of each bar graph.

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