Liver Effects of Clinical Drugs Differentiated in Human Liver Slices
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 (ET...
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | http://www.mdpi.com/1422-0067/18/3/574 |
| _version_ | 1811301920027967488 |
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| author | Alison E. M. Vickers Anatoly V. Ulyanov Robyn L. Fisher |
| author_facet | Alison E. M. Vickers Anatoly V. Ulyanov Robyn L. Fisher |
| author_sort | Alison E. M. Vickers |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T07:17:33Z |
| format | Article |
| id | doaj.art-10abd7b605cd4c21a7a188d3b7a116c3 |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-13T07:17:33Z |
| publishDate | 2017-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-10abd7b605cd4c21a7a188d3b7a116c32022-12-22T02:56:42ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-03-0118357410.3390/ijms18030574ijms18030574Liver Effects of Clinical Drugs Differentiated in Human Liver SlicesAlison E. M. Vickers0Anatoly V. Ulyanov1Robyn L. Fisher2Human Translational Models LLC, P.O. Box 4593, Irvine, CA 92612, USAInova Translational Medicine Institute, Inova Hospital, Fairfax, VA 22031, USAVitron, Inc., Tucson, AZ 85747, USADrugs 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.http://www.mdpi.com/1422-0067/18/3/574human liver slicesdrug injury |
| spellingShingle | Alison E. M. Vickers Anatoly V. Ulyanov Robyn L. Fisher Liver Effects of Clinical Drugs Differentiated in Human Liver Slices International Journal of Molecular Sciences human liver slices drug injury |
| title | Liver Effects of Clinical Drugs Differentiated in Human Liver Slices |
| title_full | Liver Effects of Clinical Drugs Differentiated in Human Liver Slices |
| title_fullStr | Liver Effects of Clinical Drugs Differentiated in Human Liver Slices |
| title_full_unstemmed | Liver Effects of Clinical Drugs Differentiated in Human Liver Slices |
| title_short | Liver Effects of Clinical Drugs Differentiated in Human Liver Slices |
| title_sort | liver effects of clinical drugs differentiated in human liver slices |
| topic | human liver slices drug injury |
| url | http://www.mdpi.com/1422-0067/18/3/574 |
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