Use of Sandwich-Cultured Hepatocytes To Evaluate Impaired Bile Acid Transport as a Mechanism of Drug-Induced Hepatotoxicity

Marion, Tracy L.; Leslie, Elaine M.; Brouwer, Kim L. R.

doi:10.1021/mp0700357

Cited by 89 publications

(74 citation statements)

References 47 publications

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“…Interestingly, BEI value for CF in HepaRG cells (34.4 %) was nearly identical to CF BEI value reported in sandwich-cultured human hepatocytes (BEI=34%) (Hoffmaster et al, 2004), which suggests that MRP2 is similarly active in these primary human hepatocytes and in HepaRG cells. By contrast, taurocholate BEI values in sandwich-cultured human hepatocytes (around 70-75%) (Marion et al, 2007) are rather higher than that found in HepaRG cells (BEI=29.2%), which likely indicates a lower BSEP activity in HepaRG cells, consistent with the down-regulation of BSEP mRNA expression observed in these hepatoma cells (Fig. 1B).…”

Section: Resultssupporting

confidence: 61%

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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Section: Resultssupporting

confidence: 61%

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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“…The biliary excretion of micafungin was inhibited by 90% with the Bsep inhibitor taurocholate (Marion et al, 2007) and by ϳ50% with GF120918 (10 M), a known inhibitor for P-gp and BCRP at this concentration (Ahmed-Belkacem et al, 2006) (Fig. 5A).…”

Section: Resultsmentioning

confidence: 95%

In Vitro Investigation of the Hepatobiliary Disposition Mechanisms of the Antifungal Agent Micafungin in Humans and Rats

Yanni¹,

Augustijns²,

Benjamin³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The purpose of the present study was to elucidate the transport mechanisms responsible for elimination of micafungin, a new semisynthetic echinocandin antifungal agent, which is predominantly cleared by biliary excretion in humans and rats. In vitro studies using sandwich-cultured rat and human hepatocytes were conducted. Micafungin uptake occurred primarily (ϳ75%) by transporter-mediated mechanisms in rat and human. Micafungin uptake into hepatocytes was inhibited by taurocholate (K i ‫؍‬ 61 M), Na

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“…Because sandwich-cultured hepatocytes [(SCH) B-CLEAR; Qualyst, Inc., Durham, NC] maintain the expression and function of key uptake and efflux transporters relative to in vivo, it is the most relevant system to evaluate and predict the potential of a compound to cause transporter-based liver toxicity. Several reports have described the use of SCH to assess the effect of compounds on the inhibition of bile acid transport, albeit using different methodologies (Kostrubsky et al, 2003(Kostrubsky et al, , 2006Kemp et al, 2005;McRae et al, 2006;Marion et al, 2007). For example, Kostrubsky et al (2006) used SCH to evaluate the potential of drugs to inhibit bile acid transport.…”

mentioning

confidence: 99%

An In Vitro Assay to Assess Transporter-Based Cholestatic Hepatotoxicity Using Sandwich-Cultured Rat Hepatocytes

Ansede¹,

Smith²,

Perry³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Drug-induced cholestasis can result from the inhibition of biliary efflux of bile acids in the liver. Drugs may inhibit the hepatic uptake and/or the biliary efflux of bile acids resulting in an increase in serum concentrations. However, it is the intracellular concentration of bile acids that results in hepatotoxicity, and thus serum concentrations may not necessarily be an appropriate indicator of hepatotoxicity. In this study, sandwich-cultured rat hepatocytes were used as an in vitro model to assess the cholestatic potential of drugs using deuterium-labeled sodium taurocholate (d 8 -TCA) as a probe for bile acid transport. Eight drugs were tested as putative inhibitors of d 8 -TCA uptake and efflux. The hepatobiliary disposition of d 8 -TCA in the absence and presence of drugs was measured by using liquid chromatography/tandem mass spectrometry, and the accumulation (hepatocytes and hepatocytes plus bile), biliary excretion index (BEI), and in vitro biliary clearance (Cl biliary ) were reported. Compounds were classified based on inhibition of uptake, efflux, or a combination of both processes. Cyclosporine A and glyburide showed a decrease in total (hepatocytes plus bile) accumulation, an increase in intracellular (hepatocytes only) accumulation, and a decrease in BEI and Cl biliary of d 8 -TCA, suggesting that efflux was primarily affected. Erythromycin estolate, troglitazone, and bosentan resulted in a decrease in accumulation (total and intracellular), BEI, and Cl biliary of d 8 -TCA, suggesting that uptake was primarily affected. Determination of a compound's relative effect on bile acid uptake, efflux, and direct determination of alterations in intracellular amounts of bile acids may provide useful mechanistic information on compounds that cause increases in serum bile acids.

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Use of Sandwich-Cultured Hepatocytes To Evaluate Impaired Bile Acid Transport as a Mechanism of Drug-Induced Hepatotoxicity

Cited by 89 publications

References 47 publications

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

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

In Vitro Investigation of the Hepatobiliary Disposition Mechanisms of the Antifungal Agent Micafungin in Humans and Rats

An In Vitro Assay to Assess Transporter-Based Cholestatic Hepatotoxicity Using Sandwich-Cultured Rat Hepatocytes

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