title: Liver Effects of Clinical Drugs Differentiated in Human Liver Slices.
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.
authors.affiliation: Human Translational Models LLC, P.O. Box 4593, Irvine, CA 92612, USA. aemvickers@me.com.
authors.forename: Alison E M
authors.initials: AE
authors.lastname: Vickers
authors.affiliation: Inova Translational Medicine Institute, Inova Hospital, Fairfax, VA 22031, USA.
authors.forename: Anatoly V
authors.initials: AV
authors.lastname: Ulyanov
authors.affiliation: Vitron, Inc., Tucson, AZ 85747, USA.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Fisher
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004249:DNA Damage; D064420:Drug-Related Side Effects and Adverse Reactions; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D015415:Biomarkers; D000255:Adenosine Triphosphate; D005978:Glutathione
keywords: drug injury; human liver slices