The human hepatoma HepaRG cells: A highly differentiated model for studies of liver metabolism and toxicity of xenobiotics

Guillouzo, André; Corlu, Anne; Aninat, Caroline; Glaise, Denise; Morel, Franck; Guguen‐Guillouzo, Christiane

doi:10.1016/j.cbi.2006.12.003

Cited by 554 publications

(419 citation statements)

References 22 publications

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“…Future work may include testing our cell and assay system with more DILI-positive and -negative compounds, although the number of compounds tested is on par with other research in this area, where an average of eight compounds are tested per experiment. 18,19,24,26,[32][33][34][35][36][37][38] Interlaboratory comparison between the few hepatotoxicity studies conducted on 3D HepaRGs and 3D primary hepatocytes revealed similarities and differences in the reported IC 50 values ( Table 3). While the reported IC 50 values for tetracycline were similar in the 3D HepaRG studies, the amiodarone and rosiglitazone results varied, with our 3D HepaRG cells responding more sensitively to the liver toxins by one to two orders of magnitude than those of Mueller et al 36 and Gunness et al 33 The differing IC 50 values for rosiglitazone and amiodarone may be due to the spheroid generation method (e.g., hanging drop method, U-bottom, additive manufacturing, and biomaterial scaffolding), spheroid maturity, cell culture conditions, and viability endpoint measurement (e.g., ATP depletion and albumin production).…”

Section: Discussionmentioning

confidence: 99%

“…HepaRG cells are a human cell line derived from a hepatocellular carcinoma that express functional liver markers, such as several cytochrome P450 (CYP) and Phase II enzymes, nuclear receptors, and membrane transporters. 18,19 When used for cytochrome P450 3A4 (CYP3A4) induction studies, HepaRG cells were found to be an excellent surrogate for primary human hepatocytes. 20 Methods for creating the 3D tissues vary from using labor-intensive single-spheroid-per-well techniques to biomaterial-reliant approaches.…”

Section: Introductionmentioning

confidence: 99%

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An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D

Ott¹,

Ramachandran²,

Stehno‐Bittel

2017

SLAS Discovery

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Drug-induced liver injury (DILI) and drug-drug interactions (DDIs) are concerns when developing safe and efficacious compounds. We have developed an automated multiplex assay to detect hepatotoxicity (i.e., ATP depletion) and metabolism (i.e., cytochrome P450 1A [CYP1A] and cytochrome P450 3A4 [CYP3A4] enzyme activity) in two-dimensional (2D) and three-dimensional (3D) cell cultures. HepaRG cells were cultured in our proprietary micromold plates and produced spheroids. HepaRG cells, in 2D or 3D, expressed liver-specific proteins throughout the culture period, although 3D cultures consistently exhibited higher albumin secretion and CYP1A/CYP3A4 enzyme activity than 2D cultures. Once the spheroid hepatic quality was assessed, 2D and 3D HepaRGs were challenged to a panel of DILI-and CYP-inducing compounds for 7 days. The 3D HepaRG model had a 70% sensitivity to liver toxins at 7 days, while the 2D model had a 60% sensitivity. In both the 2D and 3D HepaRG models, 83% of compounds were predicted to be CYP inducers after 7 days of compound exposure. Combined, our results demonstrate that an automated multiplexed liver spheroid system is a promising cell-based method to evaluate DILI and DDI for early-stage drug discovery.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D

Ott¹,

Ramachandran²,

Stehno‐Bittel

2017

SLAS Discovery

View full text Add to dashboard Cite

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“…In particular, they are able to express numerous P450 cytochromes, allowing the performance of many normal metabolic liver functions such as the production of phase I and II enzymes and transmembrane transport proteins, unlike other hepatocyte cell lines such as HepG2 (Guillouzo et al 2007;Kanebratt and Andersson 2008;Turpeinen et al 2009;Jennen et al 2010). …”

Section: Discussionmentioning

confidence: 99%

Biocompatibility assessment of functionalized magnetic mesoporous silica nanoparticles in human HepaRG cells

et al. 2017

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Magnetic mesoporous silica nanoparticles (M-MSNs) are a promising class of nanoparticles for drug delivery. However, a deep understanding of the toxicological mechanisms of action of these nanocarriers is essential, especially in the liver. The potential toxicity on HepaRG cells of pristine, pegylated (PEG), and lipid (DMPC) M-MSNs were compared. Based on MTT assay and real-time cell impedance, none of these NPs presented an extensive toxicity on hepatic cells. However, we observed by transmission electron microscopy (TEM) that the DMPC and pristine M-MSNs were greatly internalized. In comparison, PEG M-MSNs showed a slower cellular uptake. Whole gene expression profiling revealed the M-MSNs molecular modes of action in a time-and dose-dependent manner. The lowest dose tested (1.6 mg/cm 2 ) induced no molecular effect and was defined as 'No Observed Transcriptional Effect level.' The dose 16 mg/cm 2 revealed nascent but transient effects. At the highest dose (80 mg/cm 2 ), adverse effects have clearly arisen and increased over time. The limit of biocompatibility for HepaRG cells could be set at 16 mg/cm 2 for these NPs. Thanks to a comparative pathway-driven analysis, we highlighted the sequence of events that leads to the disruption of hepatobiliary system, elicited by the three types of MMSNs, at the highest dose. The Adverse Outcome Pathway of hepatic cholestasis was implicated. Toxicogenomics applied to cell cultures is an effective tool to characterize and compare the modes of action of many substances. We propose this strategy as an asset for upstream selection of the safest nanocarriers in the framework of regulation for nanobiosafety. ARTICLE HISTORY

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“…In addition, these cells are phenotypically unstable and have a limited life span [11]. Therefore, immortalized human liver cell lines, including HepG2 [12,13], Fa2N-4 [14], and HepaRG [15] have become increasingly popular as in vitro models to study human liver function and toxicity. These cell lines are readily available and can be kept in culture for long periods of time, but they suffer from genotypical instability and decreased or even absent metabolic capacity.…”

Section: Introductionmentioning

confidence: 99%

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

et al. 2015

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The human hepatoma HepaRG cells: A highly differentiated model for studies of liver metabolism and toxicity of xenobiotics

Cited by 554 publications

References 22 publications

An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D

An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D

Biocompatibility assessment of functionalized magnetic mesoporous silica nanoparticles in human HepaRG cells

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

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