Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes

Richert, Lysiane; Lamboley, C; Viollon-Abadie, Catherine; Grass, Peter; Hartmann, Nicole; Laurent, Stéphane; Heyd, Bruno; Mantion, Georges; Chibout, Salah-Dine; Staedtler, Frank

doi:10.1016/s0041-008x(03)00231-x

Cited by 74 publications

(52 citation statements)

References 43 publications

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“…Our results further confirmed that primary cultures of hepatocytes can be considered as the gold standard for DME induction studies in vitro (Richert et al, 2003;Castell et al, 2006;Tuschl and Mueller, 2006). Therefore, we extended the evaluation of the response of P450s and nuclear receptor expression to fenofibrate and EMD to primary cultures of human hepatocytes.…”

Section: Discussionsupporting

confidence: 80%

“…During the past decade, primary cultures of isolated human hepatocytes have proven to be a valuable model to study the inducing potential of drugs on different P450 isozymes (e.g., LeCluyse et al, 2000LeCluyse et al, , 2005Richert et al, 2003Richert et al, , 2006Hewitt et al, 2007). Major families of inducers have been identified, and transcription factors involved in specific induction pathways have been discovered (Waxman, 1999), such as the arylhydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor (PPAR) ␣.…”

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confidence: 99%

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Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Richert¹,

Tuschl²,

Viollon-Abadie³

et al. 2008

Drug Metabolism and Disposition

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ABSTRACT:Induction of drug-metabolizing enzymes (DMEs) is highly speciesspecific and can lead to drug-drug interaction and toxicities. In this series of studies we tested the species specificity of the antidiabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR) ␣/␥ agonist (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949, EMD) with regard to the induction of gene expression and activities of DMEs, their regulators, and typical PPAR target genes. EMD clearly induced PPAR␣ target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (P450) 4A. CYP2C and CYP3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 weeks but not after a 4-week treatment, a fact also observed in human hepatocytes after 72 h but not 24 h of EMD treatment. In human hepatocyte cultures, EMD showed similar gene expression profiles and induction of P450 activities as in monkeys, indicating that the monkey is predictive for human P450 induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPAR␣ agonist fenofibrate in primary rat and human hepatocyte cultures. In conclusion, these data showed an excellent correlation of in vivo data on DME gene expression and activity levels with results generated in hepatocyte monolayer cultures, enabling a solid estimation of human P450 induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible P450s, with evidence of CYP3A and CYP2C inducibility by PPAR␣ agonists in monkeys and humans.

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Richert¹,

Tuschl²,

Viollon-Abadie³

et al. 2008

Drug Metabolism and Disposition

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“…In addition, in agreement with other reports, transcripts of additional P450s were found to be increased in Liverbeads but usually only after prolonged treatment and at a lower extent compared with the major P450s. For example, we observed an increase in mRNA levels of Cyp2b1 with BNF and CLO, which was in agreement with previously published data (Richert et al, 2003(Richert et al, , 2009. The slight increase of Cyp1a1 by PHE could be related to its PB-like properties.…”

Section: Downloaded Fromsupporting

confidence: 93%

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Khansa¹,

Blanck²,

Bars³

2010

Drug Metabolism and Disposition

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ABSTRACT:Cryopreserved rat hepatocytes entrapped within an alginate matrix, commercially available as Liverbeads, were evaluated for their relevance as a screening tool for gene induction in vitro, using quantitative real-time reverse transcriptase-polymerase chain reaction. They were treated with the reference compounds ␤-naphthoflavone (BNF), phenobarbital (PB), pregnenolone 16␣-carbonitrile (PCN), and clofibric acid (CLO) and analyzed for mRNA levels of Cyp1a1, Cyp2b1, Cyp3a1, Cyp4a1, Ugt1a6, and Ugt2b1. In addition, for PB and PCN, the results were compared with those obtained in rat liver in vivo. For each inducer, the gene induction profiles obtained with the Liverbeads in vitro model were time-and dose-dependent. The in vitro gene expression profiles confirmed the corresponding known P450 and UGT induction by each reference compound.

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“…Three lists of probe sets of RG U34A arrays are selected from the literature whose signals were reported to be increased by certain chemical treatments: i) carcinogenicity-related gene probe sets (Ellinger-Ziegelbauer et al, 2004), ii) PPARα-regulated gene probe sets (Richert et al, 2003), and iii) glutathione deficiency-correlated gene probe sets (Kiyosawa et al, 2004a). The information for the selected probe sets is summarized in Table 2, and lists of the probe sets for each biomarker gene set are presented from Table 3 to Table 5.…”

Section: Biomarker Gene Setsmentioning

confidence: 99%

Utilization of a One-Dimensional Score for Surveying Chemical-Induced Changes in Expression Levels of Multiple Biomarker Gene Sets Using a Large-Scale Toxicogenomics Database

et al. 2006

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-A large-scale toxicogenomcis database has now been constructed in the Toxicogenomics Project in Japan (TGP). To facilitate the analytical procedures for such large-scale microarray data, we developed a simple one-dimensional score, named TGP1 which expresses the trend of the changes in expression of biomarker genes as a whole. To evaluate the usefulness of the TGP1 score, microarray data of rat liver and rat hepatocytes deposited in the TGP database were scored for three biomarker gene sets, i.e., carcinogenesis-related, PPARα-regulated and glutathione depletion-related gene sets. The TGP1 scoring system gave reasonable results, i.e., the scores for carcinogenesis-related genes were high in omeprazole-, chlorpromazine-, hexachlorobenzene-, sulfasalazine-and Wy-14,643-treated rat livers, that for PPARα-regulated genes were high in clofibrate-, Wy-14,643-, gemfibrozil-, benzbromarone-and aspirintreated rat livers as well as rat hepatocytes, and for glutathione deficiency-related genes were high in omeprazole-, bromobenzene-, acetaminophen-and coumarin-treated rat liver. We concluded that the TGP1 score is useful for surveying the expression changes in multiple biomarker gene sets for a large-scale toxicogenomics database, which would reduce the time of doing conventional multivariate statistical analysis. In addition, the TGP1 score can be applied to screening of compatible biomarker gene sets between rat liver and rat hepatocytes, like PPARα-regulated gene sets, which will allow us to develop an appropriate in vitro system for drug safety assessment in vivo.

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Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes

Cited by 74 publications

References 43 publications

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Utilization of a One-Dimensional Score for Surveying Chemical-Induced Changes in Expression Levels of Multiple Biomarker Gene Sets Using a Large-Scale Toxicogenomics Database

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