Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

Vickers, Alison E. M.; Ulyanov, Anatoly; Fisher, Ron

doi:10.3390/ijms18030574

Cited by 13 publications

(13 citation statements)

References 80 publications

(108 reference statements)

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“…Drug induced injury and repair were investigated in human liver slices exposed to APAP (1 mM) or DCF (1 mM). The doses of the drugs for this study were selected from literature citing high plasma concentrations associated with hepatotoxicity and from previous rat and human liver slice studies exhibiting concentration and time response changes in tissue function [2,15,19,20,21,22,23,30]. Both drugs were tested side-by-side in each human liver, and the drugs were dosed daily to increase the overall stress on liver slice function.…”

Section: Discussionmentioning

confidence: 99%

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Progression of Repair and Injury in Human Liver Slices

Vickers¹,

Ulyanov

Fisher³

2018

IJMS

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Human liver slice function was stressed by daily dosing of acetaminophen (APAP) or diclofenac (DCF) to investigate injury and repair. Initially, untreated human liver and kidney slices were evaluated with the global human U133A array to assess the extended culture conditions. Then, drug induced injury and signals of repair in human liver slices exposed to APAP or DCF (1 mM) were evaluated via specific gene expression arrays. In culture, the untreated human liver and kidney slices remained differentiated and gene expression indicated that repair pathways were activated in both tissues. Morphologically the human liver slices exhibited evidence of repair and regeneration, while kidney slices did not. APAP and DCF exposure caused a direct multi-factorial response. APAP and DCF induced gene expression changes in transporters, oxidative stress and mitochondria energy. DCF caused a greater effect on heat shock and endoplasmic reticulum (ER) stress gene expression. Concerning wound repair, APAP caused a mild repression of gene expression; DCF suppressed the expression of matrix collagen genes, the remodeling metalloproteases, cell adhesion integrins, indicating a greater hinderance to wound repair than APAP. Thus, human liver slices are a relevant model to investigate the mechanisms of drug-induced injury and repair.

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Section: Discussionmentioning

confidence: 99%

“…Several targets of dysfunction and underlying mechanisms were identified. This study, with three days of dosing, stressed the human liver slices more than the previous two days of dosing, as evidence by the increased number of significant gene changes [30].…”

Section: Discussionmentioning

confidence: 99%

Progression of Repair and Injury in Human Liver Slices

Vickers¹,

Ulyanov

Fisher³

2018

IJMS

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“…Similarly, human liver slices (hLS) have proven valuable to the study of viral life cycles, the assessment of antiviral drugs efficacy [69], and monitoring of local innate immune responses [70]. An elegant study [71] tested 8 approved drugs with known liver-related effects in hLS by assessing relevant markers of oxidative stress, mitochondrial function, and drug metabolism. The observed characteristics induced by reference drugs may help to evaluate the safety and dosing of new compounds thereby selecting drug candidates with the widest safety margin.…”

Section: Current Applications Of Human-based Test Models In Pharmacolmentioning

confidence: 99%

3D organ models—Revolution in pharmacological research?

Weinhart

Hocke

Hippenstiel

et al. 2019

Pharmacological Research

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A B S T R A C T 3D organ models have gained increasing attention as novel preclinical test systems and alternatives to animal testing. Over the years, many excellent in vitro tissue models have been developed. In parallel, microfluidic organ-on-a-chip tissue cultures have gained increasing interest for their ability to house several organ models on a single device and interlink these within a human-like environment. In contrast to these advancements, the development of human disease models is still in its infancy. Although major advances have recently been made, efforts still need to be intensified. Human disease models have proven valuable for their ability to closely mimic disease patterns in vitro, permitting the study of pathophysiological features and new treatment options. Although animal studies remain the gold standard for preclinical testing, they have major drawbacks such as high cost and ongoing controversy over their predictive value for several human conditions. Moreover, there is growing political and social pressure to develop alternatives to animal models, clearly promoting the search for valid, cost-efficient and easy-to-handle systems lacking interspecies-related differences.In this review, we discuss the current state of the art regarding 3D organ as well as the opportunities, limitations and future implications of their use.

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“…Precision-cut liver slices (PCLS) are a three-dimensional multicellular model with preserved tissue architecture as well as cell–cell and cell–matrix interactions that maintain and mimic liver in vivo functions. [1,2] The applicability of PCLS includes toxicity, inflammation and oxidative stress [3,4,5,6], and fibrosis as well as expression changes upon short-term or prolonged incubation of PCLS [7,8,9,10,11,12].…”

Section: Introductionmentioning

confidence: 99%

The Selection and Validation of Reference Genes for mRNA and microRNA Expression Studies in Human Liver Slices Using RT-qPCR

Zárybnický

Matoušková

Ambrož

et al. 2019

Genes

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The selection of a suitable combination of reference genes (RGs) for data normalization is a crucial step for obtaining reliable and reproducible results from transcriptional response analysis using a reverse transcription-quantitative polymerase chain reaction. This is especially so if a three-dimensional multicellular model prepared from liver tissues originating from biologically diverse human individuals is used. The mRNA and miRNA RGs stability were studied in thirty-five human liver tissue samples and twelve precision-cut human liver slices (PCLS) treated for 24 h with dimethyl sulfoxide (controls) and PCLS treated with β-naphthoflavone (10 µM) or rifampicin (10 µM) as cytochrome P450 (CYP) inducers. Validation of RGs was performed by an expression analysis of CYP3A4 and CYP1A2 on rifampicin and β-naphthoflavone induction, respectively. Regarding mRNA, the best combination of RGs for the controls was YWHAZ and B2M, while YWHAZ and ACTB were selected for the liver samples and treated PCLS. Stability of all candidate miRNA RGs was comparable or better than that of generally used short non-coding RNA U6. The best combination for the control PCLS was miR-16-5p and miR-152-3p, in contrast to the miR-16-5b and miR-23b-3p selected for the treated PCLS. Our results showed that the candidate RGs were rather stable, especially for miRNA in human PCLS.

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Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

Cited by 13 publications

References 80 publications

Progression of Repair and Injury in Human Liver Slices

Progression of Repair and Injury in Human Liver Slices

3D organ models—Revolution in pharmacological research?

The Selection and Validation of Reference Genes for mRNA and microRNA Expression Studies in Human Liver Slices Using RT-qPCR

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