Highlight report: prediction of drug induced liver injury (DILI) with human hepatocytes in vitro

Albrecht, Wiebke

doi:10.1007/s00204-017-2132-5

Cited by 3 publications

(2 citation statements)

References 19 publications

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“…In order to improve DILI prediction, numerous attempts have been undertaken such as to develop tools for risk assessment based on biomarkers [2,7,8] and to integrate experimental data into mathematical models [9]. Currently, many research groups are focusing on in vitro DILI models with human hepatocytes [10] because especially the risk for idiosyncratic DILI turned out to be almost undetectable in preclinical animal experiments [11,12]. In order to assess the effect of liver biotransformation on drug hepatotoxicity, six different cytochrome P450 (CYP) isoenzymes are in focus.…”

Section: Introductionmentioning

confidence: 99%

Human hepatocyte systems for in vitro toxicology analysis

Kammerer

Küpper

2018

JCB

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Drug induced liver injury (DILI) is still the leading single cause of drug failure during clinical phases and after market approval. Currently, many laboratories aim to develop appropriate in vitro systems to predict drug hepatotoxicity. Primary human hepatocytes are still the gold standard, but they have substantial disadvantages such as rapid dedifferentiation in vitro and lack of cell proliferation. In addition to primary human hepatocytes, liver cancer-derived cell lines such as HepG2, cytochrome P450 (CYP450) overexpressing HepG2 cell clones and HepaRG were studied intensively. In contrast to HepG2, HepaRG show promising characteristics of differentiated primary human hepatocytes, but they represent only one donor. There is some hope that this lack of donor variability can be solved by the use of iPS-derived hepatocytes. However, iPS technology still seems to need some improvement to produce physiologically relevant hepatocytes. Upcyte hepatocytes represent the most recent technical advancement combining some features of primary human hepatocytes such as physiological activity and donor variability with the ability of cell lines for extended proliferation. Altogether, more work is needed to develop and validate appropriate in vitro systems for precise prediction of DILI risk.

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Section: Introductionmentioning

confidence: 99%

Human hepatocyte systems for in vitro toxicology analysis

Kammerer

Küpper

2018

JCB

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“…For hepatitis B, in vitro models established in primary human hepatocytes (PHHs) and differentiated HepaRG cells (dHRGs) are highly useful as platforms for HBV drug discovery since they are permissive to HBV infection and reproduce a viral life cycle that is dependent on cccDNA. These better represent in vivo hepatocytes compared to hepatoma cell lines as both dHRGs and PHHs express hepatic markers and retain intact immune response pathways. − In addition, dHRGs and PHHs have been utilized to evaluate the quantitative pharmacokinetic, , metabolic, , and toxicologic profiles − of advanced candidate compounds during discovery and optimization stages. The resulting data enable dosing regimen, biomarker, and safety requirements to be established.…”

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confidence: 99%

P450s under Restriction (PURE) Screen Using HepaRG and Primary Human Hepatocytes for Discovery of Novel HBV Antivirals

Hartman

Kuduk

Espiritu

et al. 2020

ACS Med. Chem. Lett.

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Herein is reported a novel screening paradigm PURE (P450s under restriction) for the identification and optimization of hits as part of a hepatitis B virus (HBV) antiviral discovery program. To closely represent in vivo hepatocytes, differentiated HepaRG cells (dHRGs) and primary human hepatocytes (PHHs) were used as the basis for an HBV infection system. However, a significant challenge arose during potency evaluation in using cultured dHRGs and PHHs as screening platforms because, as with hepatocytes in vivo, these cells express active cytochrome P450 enzymes and thus can metabolize test compounds. The observed antiviral effects may be the cumulative result of a dynamic pool of parent compound and metabolites thus confounding structure activity relationship (SAR) interpretation and subsequent optimization design initiatives. We show here that PURE methodology restricts metabolism of HBV-infected dHRGs and PHHs and thus provides highly informative potency data for decision-making on key representative antiviral compounds.

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