Next Article in Journal
The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis
Next Article in Special Issue
Inferring Genes and Biological Functions That Are Sensitive to the Severity of Toxicity Symptoms
Previous Article in Journal
Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity
Previous Article in Special Issue
Sensitivity of Quantitative Signal Detection in Regards to Pharmacological Neuroenhancement
Open AccessArticle

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

1
Human Translational Models LLC, P.O. Box 4593, Irvine, CA 92612, USA
2
Inova Translational Medicine Institute, Inova Hospital, Fairfax, VA 22031, USA
3
Vitron, Inc., Tucson, AZ 85747, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Satohiro Masuda
Int. J. Mol. Sci. 2017, 18(3), 574; https://doi.org/10.3390/ijms18030574
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)
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
Show Figures

Graphical abstract

MDPI and ACS Style

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.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop