Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro l...

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Published inFrontiers in medical technology Vol. 2; p. 611913
Main Authors Cox, Christopher R., Lynch, Stephen, Goldring, Christopher, Sharma, Parveen
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 30.11.2020
Subjects
Medical Technology
3D
DILI
hepatocyte
in-vitro
liver
metabolism
spheroids
HLC
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Abstract Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro . This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
AbstractList Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro . This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional liver models fall short of their counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, . This review will discuss the use of 3D models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
Author Goldring, Christopher
Cox, Christopher R.
Sharma, Parveen
Lynch, Stephen
AuthorAffiliation 2 Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool , Liverpool , United Kingdom
3 Liverpool Centre for Cardiovascular Science , Liverpool , United Kingdom
1 Department of Pharmacology and Experimental Therapeutics, MRC Centre for Drug Safety Science, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool , United Kingdom
AuthorAffiliation_xml – name: 3 Liverpool Centre for Cardiovascular Science , Liverpool , United Kingdom
– name: 1 Department of Pharmacology and Experimental Therapeutics, MRC Centre for Drug Safety Science, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool , United Kingdom
– name: 2 Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool , Liverpool , United Kingdom
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  givenname: Parveen
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Keywords 3D
DILI
hepatocyte
in-vitro
liver
metabolism
spheroids
HLC
Language English
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Snippet Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical...
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SubjectTerms Medical Technology
Title Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury
URI https://www.ncbi.nlm.nih.gov/pubmed/35047893
https://www.proquest.com/docview/2621657482
https://pubmed.ncbi.nlm.nih.gov/PMC8757888
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