Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells

Lambert, Carine; Spire, Catherine; Claude, Nancy; Guillouzo, André

doi:10.1016/j.taap.2008.11.008

Cited by 82 publications

(60 citation statements)

References 49 publications

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“…Therefore, in agreement with Dickins (2004), our results led us to hypothesize that CYP3A4 and CYP4F3B could be regulated by a common mechanism involving one or several nuclear receptors such as retinoid X receptor, pregnane X receptor, and constitutive androstane receptor. Lambert et al, (2009) showed that phenobarbital, an activator of constitutive androstane receptor and pregnane X receptor, enhanced CYP4F3B but repressed CYP4A11. Likewise, we observed that CYP4A11 expression was down-regulated in DMSO-treated cells.…”

Section: Steps Of Differentiationmentioning

confidence: 99%

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

Madec¹,

Cérec²,

Plée-Gautier³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Fatty acid microsomal -oxidation involves cytochrome P450 enzymes. Some of them belonging to the CYP4F3 family are mainly expressed in the liver, making this organ a major player in energy homeostasis and lipid metabolism. To study this important regulation pathway, we used HepaRG cells, which gradually undergo a complete differentiation process. Even at the early stage of the differentiation process, CYP4F3B generated by alternative splicing of the CYP4F3 gene represented the prevalent isoform in HepaRG cells as in the liver. Its increasing expression associated with hepatocyte differentiation status suggested a hepatic-specific control of this isoform. As in liver microsomes, the catalytic hydroxylation of the CYP4F3B substrate [1-

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Section: Steps Of Differentiationmentioning

confidence: 99%

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

Madec¹,

Cérec²,

Plée-Gautier³

et al. 2011

Drug Metab Dispos

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“…Otherwise, HepaRG cells have been shown to be fully responsive to physiological, pharmacological or toxicological stimuli regulating hepatic transporter expression (Fardel and Le Vee, 2009;Lambert et al, 2009 …”

Section: Resultsmentioning

confidence: 99%

Differential regulation of drug transporter expression by all-trans retinoic acid in hepatoma HepaRG cells and human hepatocytes

Vée

Jouan

Stieger³

et al. 2013

European Journal of Pharmaceutical Sciences

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All-trans retinoic acid (atRA) is the active form of vitamin A, known to activate retinoid receptors, especially the heterodimer retinoid X receptor (RXR):retinoic acid receptor (RAR) that otherwise may play a role in regulation of some drug transporters. The present study was designed to characterize the nature of human hepatic transporters that may be targeted by atRA and the heterodimer RXR:RAR. Exposure of human hepatoma HepaRG cells and primary human hepatocytes to 5 M atRA down-regulated mRNA levels of various sinusoidal solute carrier (SLC) influx transporters, including organic anion transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1 and organic anion transporter (OAT) 2, and induced those of the canalicular breast cancer resistance protein (BCRP). The retinoid concomitantly reduced protein expression of OATP2B1 and OATP1B1 and activity of OATPs and OCT1 and induced BCRP protein expression in HepaRG cells. Some transporters such as OATP1B3 and the bile salt export pump (BSEP) were however down-regulated by atRA in primary human hepatocytes, but induced in HepaRG cells, thus pointing out discrepancies between these two liver cell models in terms of detoxifying protein regulation. atRA-mediated repressions of OATP2B1, OATP1B1, OAT2 and OCT1 mRNA expression were finally shown to be counteracted by knocking-down expression of RAR and RXR through siRNA transfection in HepaRG cells. atRA thus differentially regulated human hepatic drug transporters, mainly in a RXR:RAR-dependent manner, therefore establishing retinoids and retinoid receptors as modulators of liver drug transporter expression.

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“…Activation of rodent CAR produces a cascade of alterations in the liver including gene transcription and increased hepatocellular proliferation in rodents, a critical event in the development of liver tumors (Whysner et al 1996, Cohen 2010, Elcombe et al 2014. In humans, PB results in activation of CAR and PXR leading to the induction of Cyp enzymes as in rodents; however, a diff erent response is induced in humans compared to that of rodents (Lambert et al 2009) and, importantly, there is no evidence of increased hepatocellular proliferation. Extensive human epidemiologic studies at PB exposure levels similar to those used in rodent bioassays did not reveal increased cancer risks (Whysner et al 1996, Lamminpaa et al 2002.…”

Section: Key Events For Chemicals Acting Through the Carmentioning

confidence: 99%

“…The key events in CAR-mediated hepatocellular carcinogenesis include activation of CAR (as measured using induction of Cyp2b isoforms), leading to increased hepatocellular proliferation with subsequent induction of proliferative lesions in the liver including foci, adenomas, and carcinomas. On the other hand, although PB in humans results in activation of CAR and PXR leading to the induction of Cyp enzymes, a diff erent response is induced in humans compared to that of rodents (Lambert et al 2009) and, importantly, there is no evidence of increased hepatocellular proliferation in humans or primary human hepatocytes in vitro (reviewed in Lake 2009, Elcombe et al 2014). This fi nding was reinforced in the course of these studies with sulfoxafl or, where humanized CAR/PXR knock-in mice were refractory to the hepatocellular proliferative eff ect of sulfoxafl or, whereas wild-type mice demonstrated increased proliferation.…”

Section: Question 2 Can Human Relevance Of the Moa Be Reasonably Excmentioning

confidence: 99%

Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

LeBaron

Gollapudi

Terry³

et al. 2014

Critical Reviews in Toxicology

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Sulfoxafl or, a novel active substance that targets sap-feeding insects, induced rodent hepatotoxicity when administered at high dietary doses. Specifi cally, hepatocellular adenomas and carcinomas increased after 18 months in male and female CD-1 mice at 750 and 1250 ppm, respectively, and hepatocellular adenomas increased after 2 years in male F344 rats at 500 ppm. Studies to determine the mode of action (MoA) for these liver tumors were performed in an integrated and prospective manner as part of the standard battery of toxicology studies such that the MoA data were available prior to, or by the time of, the completion of the carcinogenicity studies. Sulfoxafl or is not genotoxic and the MoA data support the following key events in the etiology of the rodent liver tumors: (1) CAR nuclear receptor activation and (2) hepatocellular proliferation. The MoA data were evaluated in a weight of evidence approach using the Bradford Hill criteria for causation and were found to align with dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specifi city for a CAR-mediated MoA while excluding other alternate MoAs. The available data include: activation of CAR, Cyp2b induction, hepatocellular hypertrophy and hyperplasia, absence of liver eff ects in KO mice, absence of proliferation in humanized mice, and exclusion of other possible mechanisms (e.g., genotoxicity, cytotoxicity, AhR, or PPAR activation), and indicate that the identifi ed rodent liver tumor MoA for sulfoxafl or would not occur in humans. In this case, sulfoxafl or is considered not to be a potential human liver carcinogen.

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Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells

Cited by 82 publications

References 49 publications

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

Differential regulation of drug transporter expression by all-trans retinoic acid in hepatoma HepaRG cells and human hepatocytes

Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

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