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Cited by 85Drug-Induced Hepatotoxicity and Protection3D Printing in Biomedical ResearchAnimal testing and alternatives

Comprehensive Evaluation of Organotypic and Microphysiological Liver Models for Prediction of Drug-Induced Liver Injury

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Zhou, Yitian, Shen, Joanne X., Lauschke, Volker M.·2019·Frontiers in Pharmacology
DOI 10.3389/fphar.2019.01093PMC PMC6769037
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Abstract

Drug induced liver injury (DILI) is a major concern for the pharmaceutical industry and constitutes one of the most important reasons for the termination of promising drug development projects. Reliable prediction of DILI liability in preclinical stages is difficult, as current experimental model systems do not accurately reflect the molecular phenotype and functionality of the human liver. As a result, multiple drugs that passed preclinical safety evaluations failed due to liver toxicity in clinical trials or postmarketing stages in recent years. To improve the selection of molecules that are taken forward into the clinics, the development of more predictive in vitro systems that enable high-throughput screening of hepatotoxic liabilities and allow for investigative studies into DILI mechanisms has gained growing interest. Specifically, it became increasingly clear that the choice of cell types and culture method both constitute important parameters that affect the predictive power of test systems. In this review, we present current 3D culture paradigms for hepatotoxicity tests and critically evaluate their utility and performance for DILI prediction. In addition, we highlight possibilities of these emerging platforms for mechanistic evaluations of selected drug candidates and present current research directions towards the further improvement of preclinical liver safety tests. We conclude that organotypic and microphysiological liver systems have provided an important step towards more reliable DILI prediction. Furthermore, we expect that the increasing availability of comprehensive benchmarking studies will facilitate model dissemination that might eventually result in their regulatory acceptance.

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  • 3D spheroids and microtissues maintain stable expression of phase I/II enzymes, transporters, and stress/death pathways, enhancing sensitivity (80%-90%) and specificity (85%-95%) for diverse hepatotoxic mechanisms.

    “Unlike 2D cultures, 3D spheroids and microtissues maintain stable expression of phase I/II enzymes (e.g., CYP3A4, 2D6), transporters (BSEP, MRP2), and stress/death pathways, enhancing sensitivity (80%–90%) and specificity (85%–95%) for diverse hepatotoxic mechanisms (Zhou et al., 2019; Yang et al., 2023).”

    From A 3D bioengineered human liver for the study of acute and chronic drug-induced hepatotoxicity and fibrosis (2026) · cites this paper as Zhou et al., 2019

    The 'Scaffold-Free Spheroids in Multi-Well Formats' section reports stable CYP and UGT activity in HepaRG spheroids, polarized MRP2 expression in HepG2 spheroids, and detection of drugs with diverse toxicity mechanisms in primary human hepatocyte spheroids. It does not establish stable expression of the claimed stress/death pathways or the stated performance ranges. For two primary human hepatocyte spheroid assays, it instead reports sensitivity and specificity of 59% and 80%, and 69% and 100%, respectively (page unavailable in our copy). (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Zhou, Y., Shen, J. X., & Lauschke, V. M.
Affiliations
Karolinska Institutet (SE)
Corresponding author
Lauschke, Volker M.
ORCID
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2019-09-24
Volume
10
Pages
1093-1093
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2019.01093
PMC
PMC6769037
OpenAlex
W2970924609
Cited by
85
References
16
Citations by year
2026: 9 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 17 · 2021: 23 · 2020: 11 · 2019: 3
FWCI
2.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Vetenskapsrådet (2016-01153, 2016-01154)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords
drug-induced liver injury, hepatotoxicity prediction, high-throughput screening, model benchmarking

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