HepaRG cell line as an in vitro model for screening drug–drug interactions mediated by metabolic induction: Amiodarone used as a model substance

Ferreira, Ana; Rodrigues, Márcio; Silvestre, Samuel; Falcão, Amı́lcar; Alves, Gilberto

doi:10.1016/j.tiv.2014.08.004

Cited by 11 publications

(9 citation statements)

References 40 publications

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“…21,22 To date, HepaRG-Heps have been extensively used to model drug metabolism in the context of predicting hepatotoxicity and drug–drug interactions. For example, paradigm skin sensitizers, such as carbamazepine, 22 phenytoin, 23 and allopurinol, 24 are being investigated using HepaRG-Heps to discover their CYP induction potential and consequent adverse drug–drug interactions. 25,26 However, the applicability of HepaRG-Heps in the generation of reactive drug metabolites with functional readouts related to skin sensitization potential has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Bioactivation of Skin-Sensitizing Drugs to Immunogenic Reactive Metabolites

Chong

et al. 2019

ACS Omega

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The clinical use of some drugs, such as carbamazepine, phenytoin, and allopurinol, is often associated with adverse cutaneous reactions. The bioactivation of drugs into immunologically reactive metabolites by the liver is postulated to be the first step in initiating a downstream cascade of pathological immune responses. Current mechanistic understanding and the ability to predict such adverse drug cutaneous responses have been partly limited by the lack of appropriate cutaneous drug bioactivation experimental models. Although in vitro human liver models have been extensively investigated for predicting hepatotoxicity and drug–drug interactions, their ability to model the generation of antigenic reactive drug metabolites that are capable of eliciting immunological reactions is not well understood. Here, we employed a human progenitor cell (HepaRG)-derived hepatocyte model and established highly sensitive liquid chromatography-mass spectrometry analytical assays to generate and quantify different reactive metabolite species of three paradigm skin sensitizers, namely, carbamazepine, phenytoin, and allopurinol. We found that the generation of reactive drug metabolites by the HepaRG-hepatocytes was sensitive to the medium composition. In addition, a functional assay based on the activation of U937 myeloid cells into the antigen-presenting cell (APC) phenotype was established to evaluate the immunogenicity potential of the reactive drug metabolites produced by HepaRG-derived hepatocytes. We showed that the reactive drug metabolites of known skin sensitizers could significantly upregulate IL 8, IL 1β, and CD 86 expressions in U937 cells compared to the metabolites from a nonskin sensitizer (i.e., acetaminophen). Thus, the extent of APC activation by HepaRG-hepatocytes conditioned medium containing reactive drug metabolites can potentially be used to predict their skin sensitization potential.

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Section: Introductionmentioning

confidence: 99%

Hepatic Bioactivation of Skin-Sensitizing Drugs to Immunogenic Reactive Metabolites

Chong

et al. 2019

ACS Omega

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“…We have developed techniques to aggregate stable and reproducible liver spheroids, consisting of differentiated HepaRG (parenchymal) and HHSteC (non-parenchymal) cells, and to reproduce hepatic lobule equivalents, that is, the functional units of the liver 24,[31][32][33][34] . The HepaRG cell line was utilized as an in vitro model to predict cytochrome P450 (P450) enzyme induction of drugs in humans [35][36][37] . Furthermore, emulation of the fluid shear stress and interstitial Figure 8.…”

Section: Discussionmentioning

confidence: 99%

Repeated dose multi-drug testing using a microfluidic chip-based coculture of human liver and kidney proximal tubules equivalents

Lin

Zhou

Geng

et al. 2020

Sci Rep

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A microfluidic multi-organ chip emulates the tissue culture microenvironment, enables interconnection of organ equivalents and overcomes interspecies differences, making this technology a promising and powerful tool for preclinical drug screening. In this study, we established a microfluidic chip-based model that enabled non-contact cocultivation of liver spheroids and renal proximal tubule barriers in a connecting media circuit over 16 days. Meanwhile, a 14-day repeated-dose systemic administration of cyclosporine A (CsA) alone or in combination with rifampicin was performed. Toxicity profiles of the two different doses of CsA on different target organs could be discriminated and that concomitant treatment with rifampicin from day6 onwards decreased the CsA concentration and attenuated the toxicity compared with that after treatment with CsA for 14 consecutive days. The latter is manifested with the changes in cytotoxicity, cell viability and apoptosis, gene expression of metabolic enzymes and transporters, and noninvasive toxicity biomarkers. The on chip coculture of the liver and the proximal tubulus equivalents showed its potential as an effective and translational tool for repeated dose multi-drug toxicity screening in the preclinical stage of drug development.

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“…It is hard to use HepaRG for study because of its need for difficult culture conditions. However, HepaRG may represent a more promising liver model than HepG2 when evaluating hepatic drug metabolism under in vitro conditions because HepaRG possesses the metabolic capacity characteristics of primary human hepatocytes [232425]. …”

Section: Resultsmentioning

confidence: 99%

Protective effects of an ethanol extract ofAngelica keiskeiagainst acetaminophen-induced hepatotoxicity in HepG2 and HepaRG cells

et al. 2017

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BACKGROUND/OBJECTIVEAlthough Angelica keiskei (AK) has widely been utilized for the purpose of general health improvement among Asian, its functionality and mechanism of action. The aim of this study was to determine the protective effect of ethanol extract of AK (AK-Ex) on acute hepatotoxicity induced by acetaminophen (AAP) in HepG2 human hepatocellular liver carcinoma cells and HepaRG human hepatic progenitor cells.MATERIALS/METHODSAK-Ex was prepared HepG2 and HepaRG cells were cultured with various concentrations and 30 mM AAP. The protective effects of AK-Ex against AAP-induced hepatotoxicity in HepG2 and HepaRG cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, lactate dehydrogenase (LDH) assay, flow cytometry, and Western blotting.RESULTSAK-Ex, when administered prior to AAP, increased cell growth and decreased leakage of LDH in a dose-dependent manner in HepG2 and HepaRG cells against AAP-induced hepatotoxicity. AK-Ex increased the level of Bcl-2 and decreased the levels of Bax, Bok and Bik decreased the permeability of the mitochondrial membrane in HepG2 cells intoxicated with AAP. AK-Ex decreased the cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of caspase-9, -7, and -3.CONCLUSIONSThese results demonstrate that AK-Ex downregulates apoptosis via intrinsic and extrinsic pathways against AAP-induced hepatotoxicity. We suggest that AK could be a useful preventive agent against AAP-induced apoptosis in hepatocytes.

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HepaRG cell line as an in vitro model for screening drug–drug interactions mediated by metabolic induction: Amiodarone used as a model substance

Cited by 11 publications

References 40 publications

Hepatic Bioactivation of Skin-Sensitizing Drugs to Immunogenic Reactive Metabolites

Hepatic Bioactivation of Skin-Sensitizing Drugs to Immunogenic Reactive Metabolites

Repeated dose multi-drug testing using a microfluidic chip-based coculture of human liver and kidney proximal tubules equivalents

Protective effects of an ethanol extract ofAngelica keiskeiagainst acetaminophen-induced hepatotoxicity in HepG2 and HepaRG cells

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