Rozenn Jossé

Université de Rennes 1, Roazhon, Brittany, France

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Publications (18)50.9 Total impact

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    ABSTRACT: Common in vitro toxicity testing often neglects the fate and intracellular concentration of tested compounds, potentially limiting the predictability of in vitro results for in vivo extrapolation. We used in vitro long-term cultures of primary rat (PRH) and human hepatocytes (PHH) and HepaRG cells to characterise and model the biokinetic profile of ibuprofen (IBU) after single and daily repeated exposure (14 days) to two concentrations. A cross-model comparison was carried out at 100μM, roughly corresponding to the human therapeutic plasma concentration. Our results showed that IBU uptake was rapid and a dynamic equilibrium was reached within 1 or 2 days. All three cell systems efficiently metabolised IBU. In terms of species-differences, our data mirrored known in vivo results. Although no bioaccumulation was observed, IBU intracellular concentration was higher in PRH due to a 10-fold lower metabolic clearance compared to the human-derived cells. In HepaRG cells, IBU metabolism increased over time, but was not related to the treatment. In PHH, a low CYP2C9 activity, the major IBU-metabolising CYP, led to an increased cytotoxicity. A high inter-individual variability was seen in PHH, whereas HepaRG cells and PRH were more reproducible models. Although the concentrations of IBU in PRH over time differed from the concentrations found in human cells under similar exposure conditions. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology Letters 01/2015; 233(2). DOI:10.1016/j.toxlet.2015.01.006 · 3.36 Impact Factor
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    ABSTRACT: Previous works have shown that differentiated human HepaRG cells can exhibit drug metabolism activities close to those of primary human hepatocytes for several weeks at confluence. The present study was designed to evaluate their long-term functional stability and their response to repeated daily drug treatments over a 14-day period, using a transcriptomic approach. Our data show that less than 1% of the expressed genes were markedly deregulated over this two weeks period and mainly included down-regulation of genes related to the cell cycle and from 3 days, overexpression of genes involved in xenobiotic and lipid metabolism. After daily treatment with the three PPAR agonists, fenofibrate, troglitazone and rosiglitazone qualitative and/or quantitative changes in gene profiling were observed depending on the compound and duration of treatment. The highest increase in the number of deregulated genes as a function of drug treatment was seen with rosiglitazone. The most up-regulated genes common across the three compounds were mainly related to lipid and xenobiotic metabolisms. All the data support the conclusion that human HepaRG cells have an exceptional functional stability at confluence and that they are suitable for investigations on chronic effects of drugs and other chemicals. Copyright © 2015. Published by Elsevier Ltd.
    Toxicology in Vitro 01/2015; DOI:10.1016/j.tiv.2014.12.019 · 3.21 Impact Factor
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    ABSTRACT: Since drug induced liver injury is difficult to predict in animal models, more representative tests are needed to better evaluate these effects in humans. Existing in vitro systems hold great potential to detect hepatotoxicity of pharmaceuticals. In this study, the in vitro biokinetics of the model hepatotoxicant chlorpromazine (CPZ) were evaluated in three different liver cell systems after repeated exposure in order to incorporate repeated-dose testing into an in vitro assay. Primary rat and human hepatocytes, cultured in sandwich configuration and the human HepaRG cell line were treated daily with CPZ for 14days. Samples were taken from medium, cells and well plastic at specific time points after the first and last exposure. The samples were analysed by HPLC-UV to determine the amount of CPZ in these samples. Based on cytotoxicity assays, the three models were tested at 1-2μM CPZ, while the primary rat hepatocytes and the HepaRG cell line were in addition exposed to a higher concentration of 15-20μM. Overall, the mass balance of CPZ decreased in the course of 24h, indicating the metabolism of the compound within the cells. The largest decrease in parent compound was seen in the primary cultures; in the HepaRG cell cultures the mass balance only decreased to 50%. CPZ accumulated in the cells during the 14-day repeated exposure. Possible explanations for the accumulation of CPZ are a decrease in metabolism over time, inhibition of efflux transporters or binding to phospholipids. The biokinetics of CPZ differed between the three liver cell models and were influenced by specific cell properties as well as culture conditions. These results support the conclusion that in vitro biokinetics data are necessary to better interpret chemical-induced cytotoxicity data. Copyright © 2014. Published by Elsevier Ltd.
    Toxicology in Vitro 11/2014; DOI:10.1016/j.tiv.2014.08.012 · 3.21 Impact Factor
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    ABSTRACT: Humans are usually simultaneously exposed to several pesticides; consequently, combined actions between pesticides themselves or between pesticides and other chemicals need to be addressed in the risk assessment. Many pesticides are efficient activators of PXR and/or CAR, two major nuclear receptors that are also activated by other substrates. In the present work, we searched for interactions between endosulfan and methoxychlor, two organochlorine pesticides whose major routes of metabolism involve CAR- and PXR-regulated CYP3A4 and CYP2B6, and whose mechanisms of action remain poorly understood in humans. For this purpose, HepaRG cells were treated with both pesticides separately or in mixture for 24h or 2 weeks at concentrations relevant to human exposure levels. In combination they exerted synergistic cytotoxic effects. Whatever the duration of treatment both compounds increased CYP3A4 and CYP2B6 mRNA levels while they differently affected their corresponding activities. Endosulfan exerted a direct reversible inhibition of CYP3A4 activity that was confirmed in human liver microsomes. By contrast, methoxychlor induced this activity. The effects of the mixture on CYP3A4 activity were equal to the sum of those of each individual compound, suggesting an additive effect of each pesticide. Despite CYP2B6 activity was unchanged and increased with endosulfan and methoxychlor respectively, no change was observed with their mixture, supporting an antagonistic effect. Altogether, our data suggest that CAR and PXR activators endosulfan and methoxychlor can interact together and with other exogenous substrates in human hepatocytes. Their effects on CYP3A4 and CYP2B6 activities could have important consequences if extrapolated to the in vivo situation.
    Drug metabolism and disposition: the biological fate of chemicals 05/2014; 42(8). DOI:10.1124/dmd.114.057786 · 3.33 Impact Factor
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    ABSTRACT: Isomalathion is a major impurity of technical grade malathion, one of the most abundantly applied insecticides; however little is known about its hepatotoxicity. In the present study, cytotoxicity and genotoxicity of malathion and isomalathion either individually or in combination, were assessed using the metabolically competent human liver HepaRG cell line. Isomalathion reduced cell viability starting at a 100 μM concentration after a 24 h exposure. It also significantly induced caspase-3 activity in a dose-dependent manner starting at 5 μM. On the contrary, even at concentrations as high as 500 μM malathion affected neither cell viability nor caspase-3 activity. Moreover, co-exposure of both compounds resulted in decreased toxicity of isomalathion. By contrast, malathion and isomalathion either separately or in combination, slightly induced micronuclei formation at low concentrations and had additive genotoxic effects when combined at 25 μM. Individually or combined isomalathion directly inhibited activity of carboxyesterases which are involved in detoxication of malathion. In addition, transcripts of CYP2B6 and CYP3A4, two CYPs responsible for malathion phase I metabolism, were strongly induced by the mixture while isomalathion alone only moderately decreased CYP1A2 and increased CYP2B6 transcripts. However, these CYPs were not altered at the protein or activity levels. Taken altogether, our results showed that isomalathion was much more cytotoxic than malathion while both compounds had comparable genotoxic effects in HepaRG hepatocytes at low concentrations and brought further support to the importance of considering impurities and interactions during evaluation of health risks of pesticides.
    Chemico-biological interactions 12/2013; DOI:10.1016/j.cbi.2013.12.002 · 2.98 Impact Factor
  • Toxicology Letters 06/2012; 211:S197. DOI:10.1016/j.toxlet.2012.03.708 · 3.36 Impact Factor
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    ABSTRACT: Gene expression profiling has recently emerged as a promising approach to identify early target genes and discriminate genotoxic carcinogens from non-genotoxic carcinogens and non-carcinogens. However, early gene changes induced by genotoxic compounds in human liver remain largely unknown. Primary human hepatocytes and differentiated HepaRG cells were exposed to aflatoxin B1 (AFB1) that induces DNA damage following enzyme-mediated bioactivation. Gene expression profile changes induced by a 24h exposure of these hepatocyte models to 0.05 and 0.25μM AFB1 were analyzed by using oligonucleotide pangenomic microarrays. The main altered signaling pathway was the p53 pathway and related functions such as cell cycle, apoptosis and DNA repair. Direct involvement of the p53 protein in response to AFB1 was verified by using siRNA directed against p53. Among the 83 well-annotated genes commonly modulated in two pools of three human hepatocyte populations and HepaRG cells, several genes were identified as altered by AFB1 for the first time. In addition, a subset of 10 AFB1-altered genes, selected upon basis of their function or tumor suppressor role, was tested in four human hepatocyte populations and in response to other chemicals. Although they exhibited large variable inter-donor fold-changes, several of these genes, particularly FHIT, BCAS3 and SMYD3, were found to be altered by various direct and other indirect genotoxic compounds and unaffected by non-genotoxic compounds. Overall, this comprehensive analysis of early gene expression changes induced by AFB1 in human hepatocytes identified a gene subset that included several genes representing potential biomarkers of genotoxic compounds.
    Toxicology and Applied Pharmacology 11/2011; 258(2):176-87. DOI:10.1016/j.taap.2011.10.019 · 3.63 Impact Factor
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    ABSTRACT: The in vitro micronucleus test is considered as an attractive tool for genotoxicity testing of chemicals because of its simplicity of scoring and wide applicability in different cell types. However, most of the cells currently in use are devoid of the enzyme equipment required for activation of promutagens in the genotoxic metabolites. We postulated that the human HepaRG cell line, which can express xenobiotic metabolising enzymes at levels close to those found in primary human hepatocytes and has retained the indefinite growth capacity of transformed cells, could represent a more suitable model for genotoxicity testing of chemicals requiring metabolic activation. Based on the recommendations of the Organisation for Economic Co-operation and Development test guideline TG 487 for testing of chemicals, HepaRG cell cultures containing >80% mature hepatocytes were treated in situ with various chemicals for 24 h followed by a 3-day mitogenic stimulation with epidermal growth factor without cytokinesis block. In such culture conditions, HepaRG cells underwent >1.5 cell cycle per cell during the mitogenic stimulation. While non-genotoxic compounds (mannitol and staurosporine) did not increase the rate of micronucleated mononucleated cells, all aneugens (colchicine, nocodazole and dichlorodiphenyldichloroethylene) as well as the direct acting clastogen methyl methanesulfonate and clastogens requiring metabolic activation (aflatoxin B1, benzo(a)pyrene and 2-nitrofluorene) induced a statistically significant concentration-related increase in the number of mono-micronucleated cells. The micronucleus test was also performed after 7-day repeat exposure of HepaRG cells to the chemicals. Noticeably, a time-dependent effect was obtained with the three clastogens requiring metabolic activation. In conclusion, our results obtained with HepaRG hepatocytes exposed to various genotoxic compounds requiring or not bioactivation, compared favorably with those reported in various other cell types. They support the view that metabolically competent HepaRG cells have unique potential benefits for testing genotoxic compounds using the in vitro micronucleus assay.
    Mutagenesis 11/2011; 27(3):295-304. DOI:10.1093/mutage/ger076 · 3.50 Impact Factor
  • Fuel and Energy Abstracts 08/2011; 205. DOI:10.1016/j.toxlet.2011.05.393
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    ABSTRACT: Several glitazones (PPARγ agonists) and glitazars (dual PPARα/γ agonists) have been developed to treat hyperglycemia and, simultaneously, hyperglycemia and dyslipidemia, respectively. However, most have caused idiosyncratic hepatic or extrahepatic toxicities through mechanisms that remain largely unknown. Since the liver plays a key role in lipid metabolism, we analyzed changes in gene expression profiles induced by these two types of PPAR agonists in human hepatocytes. Primary human hepatocytes and the well-differentiated human hepatoma HepaRG cells were exposed to different concentrations of two PPARγ (troglitazone and rosiglitazone) and two PPARα/γ (muraglitazar and tesaglitazar) agonists for 24 h and their transcriptomes were analyzed using human pangenomic Agilent microarrays. Principal Component Analysis, hierarchical clustering and Ingenuity Pathway Analysis® revealed large inter-individual variability in the response of the human hepatocyte populations to the different compounds. Many genes involved in lipid, carbohydrate, xenobiotic and cholesterol metabolism, as well as inflammation and immunity, were regulated by both PPARγ and PPARα/γ agonists in at least a number of human hepatocyte populations and/or HepaRG cells. Only a few genes were selectively deregulated by glitazars when compared to glitazones, indicating that PPARγ and PPARα/γ agonists share most of their target genes. Moreover, some target genes thought to be regulated only in mouse or to be expressed in Kupffer cells were also found to be responsive in human hepatocytes and HepaRG cells. This first comprehensive analysis of gene regulation by PPARγ and PPARα/γ agonists favor the conclusion that glitazones and glitazars share most of their target genes and induce large differential changes in gene profiles in human hepatocytes depending on hepatocyte donor, the compound class and/or individual compound, thereby supporting the occurrence of idiosyncratic toxicity in some patients.
    PLoS ONE 04/2011; 6(4):e18816. DOI:10.1371/journal.pone.0018816 · 3.53 Impact Factor
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    ABSTRACT: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are two of the most common heterocyclic aromatic amines (HAA) produced during cooking of meat, fish and poultry. Both HAA produce different tumor profiles in rodents and are suspected to be carcinogenic in humans. In order to better understand the molecular basis of HAA toxicity, we have analyzed gene expression profiles in the metabolically competent human HepaRG cells using pangenomic oligonucleotide microarrays, after either a single (24-h) or a repeated (28-day) exposure to 10 μM PhIP or MeIQx. The most responsive genes to both HAA were downstream targets of the arylhydrocarbon receptor (AhR): CYP1A1 and CYP1A2 after both time points and CYP1B1 and ALDH3A1 after 28 days. Accordingly, CYP1A1/1A2 induction in HAA-treated HepaRG cells was prevented by chemical inhibition or small interference RNA-mediated down-regulation of the AhR. Consistently, HAA induced activity of the CYP1A1 promoter, which contains a consensus AhR-related xenobiotic-responsive element (XRE). In addition, several other genes exhibited both time-dependent and compound-specific expression changes with, however, a smaller magnitude than previously reported for the prototypical AhR target genes. These changes concerned genes mainly related to cell growth and proliferation, apoptosis, and cancer. In conclusion, these results identify the AhR gene battery as the preferential target of PhIP and MeIQx in HepaRG cells and further support the hypothesis that intake of HAA in diet might increase human cancer risk.
    Toxicology and Applied Pharmacology 11/2010; 249(1):91-100. DOI:10.1016/j.taap.2010.08.027 · 3.63 Impact Factor
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    ABSTRACT: Many chemical carcinogens require metabolic activation to form genotoxic compounds in human. Standard in vitro genotoxicity assays performed with activation systems, such as rat liver S9, are recognised to lead to a high number of false positives. The aim of this study was to evaluate the suitability of differentiated human hepatoma HepaRG cells as an in vitro model system for the detection of DNA damage induced by promutagens using the comet and the cytokinesis-block micronucleus assays. Several promutagens were tested, including aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), acrylamide, N-nitrosodimethylamine (NDMA), cyclophosphamide (CPA), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Cytotoxicity of these compounds was assessed by measuring lactate dehydrogenase leakage. A 24 h exposure was generally needed to obtain an obvious positive response in differentiated HepaRG cells in the comet and in the cytokinesis-block micronucleus assays. Comet formation was observed with all compounds except IQ. B[a]P, CPA and AFB1 showed a dose-dependent increase in micronucleated cells, whereas no increase was observed with PhIP, IQ and acrylamide. These preliminary data on genotoxicity in differentiated HepaRG cells are promising but more chemicals must be tested to determine the ability of HepaRG cells to assess genotoxicity of chemicals in humans.
    Mutagenesis 11/2010; 25(6):555-60. DOI:10.1093/mutage/geq039 · 3.50 Impact Factor
  • Toxicology Letters 07/2010; 196. DOI:10.1016/j.toxlet.2010.03.598 · 3.36 Impact Factor
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    ABSTRACT: Human exposure to heterocyclic aromatic amines (HAA) usually occurs through mixtures rather than individual compounds. However, the toxic effects and related mechanisms of co-exposure to HAA in humans remain unknown. We compared the effects of two of the most common HAA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), individually or in combination, in the metabolically competent human hepatoma HepaRG cells. Various endpoints were measured including cytotoxicity, apoptosis, oxidative stress and DNA damage by the comet assay. Moreover, the effects of PhIP and/or MeIQx on mRNA expression and activities of enzymes involved in their activation and detoxification pathways were evaluated. After a 24h treatment, PhIP and MeIQx, individually and in combination, exerted differential effects on apoptosis, oxidative stress, DNA damage and cytochrome P450 (CYP) activities. Only PhIP induced DNA damage. It was also a stronger inducer of CYP1A1 and CYP1B1 expression and activity than MeIQx. In contrast, only MeIQx exposure resulted in a significant induction of CYP1A2 activity. The combination of PhIP with MeIQx induced an oxidative stress and showed synergistic effects on apoptosis. However, PhIP-induced genotoxicity was abolished by a co-exposure with MeIQx. Such an inhibitory effect could be explained by a significant decrease in CYP1A2 activity which is responsible for PhIP genotoxicity. Our findings highlight the need to investigate interactions between HAA when assessing risks for human health and provide new insights in the mechanisms of interaction between PhIP and MeIQx.
    Toxicology and Applied Pharmacology 03/2010; 245(2):256-63. DOI:10.1016/j.taap.2010.03.008 · 3.63 Impact Factor
  • Toxicology Letters 09/2009; 189. DOI:10.1016/j.toxlet.2009.06.213 · 3.36 Impact Factor
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    ABSTRACT: The human hepatoma HepaRG cells are able to differentiate in vitro into hepatocyte-like cells and to express various liver-specific functions, including the major cytochromes P450. This study was aimed to determine whether differentiated HepaRG cells retained their specific functional capacities for a long time period at confluence. We show that expression of transcripts encoding CYP1A2, 2B6, 3A4, and 2E1, several phase II and antioxidant enzymes, membrane transporters, including organic cation transporter 1 and bile salt export pump, the nuclear receptors constitutive androstane receptor and pregnane X receptor, and aldolase B remained relatively stable for at least the 4-week confluence period tested. Similarly, activities of CYP3A4 and CYP1A2 and their responsiveness to prototypical inducers were well preserved. Aflatoxin B(1), a potent hepatotoxicant and carcinogen, induced a dose-dependent and cumulative cytotoxicity. Furthermore, at a concentration as low as 0.1 microM, this mycotoxin caused a decrease in both CYP3A4 activity and intracellular ATP associated with morphological alterations, after 14 days following every 2-day exposure. Moreover, using the comet assay, a dose-dependent DNA damage was observed after a 3-h treatment of differentiated HepaRG cells with 1 to 5 microM aflatoxin B(1) in the absence of any cell damage, and this DNA damaging effect was strongly reduced in the presence of ketoconazole, a CYP3A4 inhibitor. These results bring the first demonstration of long-term stable expression of liver-specific markers in HepaRG hepatocyte cultures maintained at confluence and show that these cells represent a suitable in vitro liver cell model for analysis of acute and chronic toxicity as well as genotoxicity of chemicals in human liver.
    Drug metabolism and disposition: the biological fate of chemicals 07/2008; 36(6):1111-8. DOI:10.1124/dmd.107.019901 · 3.33 Impact Factor
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    ABSTRACT: The human HepaRG cells represent the first human hepatoma cell line able to differentiate in vitro into hepatocyte-like cells and display hepatocyte functions. Several lines of evidence have demonstrated that HepaRG cells exhibit (i) a hepatocyte-like morphology; (ii) a greater metabolic competence for phase I and II enzyme activities; (iii) a concomitant expression of hepatic influx and efflux transporters; (iv) a good inducibility on drug metabolizing enzymes. The main objective of the present study is to determine whether HepaRG cells remain responsive to inducers of metabolizing enzymes, nuclear factors and transporters involved in chemical metabolism when maintained during three sub-cultures at confluence for several weeks. After seeding of HepaRG cells at high density (subcultures 14, 17 & 20), the differentiated HepaRG hepatocytes resulted from three end-time point cultures were treated by the following procedure (i) depletion of DMSO for reducing the basal activity; (ii) induction of HepaRG with 3 CYP model inducers (rifampicin, omeprazole, phenobarbital); (iii) incubation of treated cells with a cocktail of 8 probe substrates. Then, the effects of inducers on the mRNA expression profile of target genes (phase I, II metabolising enzymes, transporters & nuclear receptors) were quantitatively measured by RT-qPCR analysis, while the CYPs metabolic activities were assessed by LC/MSMS. Furthermore, the functional expression/activities of hepatic efflux transporters were evaluated by specific fluorescent substrates assay. Overall, our data indicate that HepaRG cells retain a stable maintenance of metabolic activity and related gene expression with subcultures (P14 to P20) as well as good inducibility of.hepatic biomarkers in response to inducers. Therefore, these results suggest that HepaRG hepatocytes should represent a valuable model for cocktail substrate-based high-throughput screening in drug metabolism induction and for the evaluation of drug transporter induction and activity in vitro.
    11th European Regional International society for the study of xenobiotics Meeting;
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    ABSTRACT: Indroduction The human HepaRG cells represent the first human hepatoma cell line able to differentiate in vitro into hepatocyte-like cells and display hepatocyte functions. Several lines of evidence have demonstrated that HepaRG cells exhibit (i) a hepatocyte-like morphology; (ii) a greater metabolic competence for phase I and II enzyme activities; (iii) a concomitant expression of hepatic influx and efflux transporters; (iv) a good inducibility on drug metabolizing enzymes (Aninat et al, 2006; Le Vee et al, 2007; Kanebratt KP et al, 2008). Objective The main objective of the present study is to determine whether HepaRG cells remain responsive to inducers of metabolizing enzymes, nuclear factors and transporters involved in chemical metabolism when maintained during three sub-cultures at confluence for several weeks. Method After seeding of HepaRG cells at high density (subcultures 14, 17 & 20), the differentiated HepaRG hepatocytes resulted from three end-time point cultures were treated by the following procedure (i) depletion of DMSO for reducing the basal activity; (ii) induction of HepaRG with 3 CYP model inducers (rifampicin, omeprazole, phenobarbital); (iii) incubation of treated cells with a cocktail of 8 probe substrates. Then, the effects of inducers on the mRNA expression profile of target genes (phase I, II metabolising enzymes, transporters & nuclear receptors) were quantitatively measured by RT-qPCR analysis, while the CYPs metabolic activities were assessed by LC/MSMS (Ari Tolonen et al, 2007). Furthermore, the functional expression/activities of hepatic efflux transporters were evaluated by specific fluorescent substrates assay (Wang E.J et al 2003; Zhang P et al 2005). Results The present study shows some very promising results: (i) A close correlation was observed between the basal mRNA levels of liver-specific markers in human fresh hepatocytes (CYPs, transporters and nuclear receptor) and HepaRG hepatocytes at day 28 of cultures; (ii) A significant and correlative induction profile was demonstrated between the target gene expression and metabolic activities by 3 tested prototypical inducers assessed by RT-PCR & “cocktail” approach; (iii) A significant and different increase of MDR1, MRP2 and BCRP in response to the inducers was observed, meanwhile the induction responses profile were similar in 3 end-point of culture periods; (iv) A specific accumulation of fluorescent substrate in canalicular spaces mediated by efflux transporters (BSEP MDR1) was observed, which indicating a good functional activity of canalicular transporters mediated bile efflux in HepaRG hepatocytes. Conclusions Overall, our results indicate that HepaRG cells retained hepatocyte like morphological and functional properties: - stable maintenance of metabolic activity and related gene expression with subcultures (P14 to P20); - a good inducibility of.hepatic biomarkers in response to inducers; - a suitable model in vitro for cocktail substrate-based high-throughput screening in drug metabolism induction; - an in vitro model for the evaluation of drug transporter induction and activity. These results support the conclusion that HepaRG hepatocytes should represent a valuable model for evaluating of induction of drug metabolising CYP enzymes & other hepatic biomarkers. Acknowledgement We acknowledge the European Community for the contribution to the funding of this work performed in “LIINTOP project”. We also thank Pr. F Zucco for her leadership in “LIINTOP project”.
    2nd Asian Pacific Regional International society for the study of xenobiotics Meeting;

Publication Stats

149 Citations
50.90 Total Impact Points

Institutions

  • 2008–2015
    • Université de Rennes 1
      • Faculty of Pharmaceutical Sciences
      Roazhon, Brittany, France
  • 2013
    • French Institute of Health and Medical Research
      • Unit of Liver, Metabolisms and Cancer
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France