Up‐regulation of multidrug resistance‐associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone

Courtois, Arnaud; Payen, Léa; Fardel, Olivier

doi:10.1016/s0014-5793(99)01295-8

Cited by 100 publications

(66 citation statements)

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“…glucocorticoid receptor which regulates a number of transporter gene expression. 44,45) By this mechanism, NO may affect the transporter expression levels. It also should be considered that IDM directly affected the hepatic expression of transporters, resulting in its reduction.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

Fujiyama

Shitara

Ito

et al. 2007

Biological & Pharmaceutical Bulletin

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Systemic administration of indomethacin (IDM) causes inflammation of the small intestine. Although the pathogenic events of IDM are more complex, it is considered that suppression of prostaglandin synthesis, mitochondrial damage and oxidative stress response are involved in it.1,2) And, generation of reactive oxygen species decreases alkaline phosphatase (ALP) activity in intestinal mucosa, followed by an attenuation of differentiation and proliferation of villus. 3,4) In addition, gram-negative bacteria-derived endotoxin also strongly induces damages of villus enterocyte and contributes to its exacerbation. 5,6) Previous studies using animal models of bowel disease involving IDM-induced intestinal injury, trinitrobenzene sulfonic acid (TNBS)-induced colitis and dextran sulfate sodium-induced colitis have shown that the enteropathy is associated with the alteration of hepatic cytochrome P450 (CYP) and been suggested the relationship of the entering bacterial endotoxin into portal vein according to an increase of intestinal epithelium permeability. [7][8][9] In contrast with CYPs, little is known about the expression of hepatic transporters in bowel injury, although drug transporters as well as metabolizing enzymes play an important role in the disposition of most drugs.Organic anion transporting polypeptides (Oatp), located in the liver sinusoidal membrane, take part in the hepatic uptake of bile acids, peptide hormones, steroid hormones and a variety of drugs.10,11) Multidrug resistance-associated protein 2 (Mrp2), located in the liver canalicular membrane, excretes a variety of organic anions including endogenous glutathione (GSH), GSH-conjugates and glucuronides into bile. 12,13) Interplay between these influx and efflux transporters is fundamental to the biliary elimination or enterohepatic recirculation of endogenous and exogenous compounds. [14][15][16] The aim of this study is to characterize the alteration in these hepatic organic anion transporters in rats with IDM-induced injury to the small intestine. The hepatic transporter function was evaluated by a pharmacokinetic study of bromosulfophthalein (BSP), and the expression of hepatic transporters for BSP was also evaluated in control and IDMtreated rats. Inflammatory mediators in the portal plasma were traced as causal candidates ultimately affecting hepatic transporter expression. MATERIALS AND METHODSChemicals IDM was purchased from Wako Pure Chemical Industries (Osaka, Japan). BSP was purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Other chemicals and solvents used were of the highest quality commercially available.In Vivo Experimental Procedures Male Sprague-Dawley rats (Japan SLC Inc., Shizuoka, Japan) weighing 235-290 g (7-8 weeks old) were used throughout the experiments. Rats were housed in an air-conditioned room (25°C) under a 12 h light-dark cycle for at least 1 week before use. Food (the MF diet, standard laboratory diet commercially available, Oriental Yeast Co., Ltd., Tokyo, Japan) and water were given ad libitum. The rats were inje...

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Section: Discussionmentioning

confidence: 99%

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

Fujiyama

Shitara

Ito

et al. 2007

Biological & Pharmaceutical Bulletin

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“…This approach assumes that membrane-associated transport systems for APAP metabolites in hepatocytes are not affected by xenobiotic treatment. With the recent identification and characterization of several apical and basolateral transporters (Muller and Jansen, 1997), it is now clear that the hepatic levels of some transport systems can be modulated by prototypical microsomal inducers such as pregnenolone 16␣-carbonitrile (Salphati and Benet, 1998), dexamethasone (Courtois et al, 1999), and phenobarbital (Ogawa et al, 2000). Therefore, these types of APAP disposition studies should be interpreted with respect to both xenobiotic inducibility of hepatic transporters and molecular mechanisms for the hepatic excretion of APAP and its metabolites.…”

mentioning

confidence: 99%

HEPATOBILIARY EXCRETION OF ACETAMINOPHEN GLUTATHIONE CONJUGATE AND ITS DERIVATIVES IN TRANSPORT-DEFICIENT (TR^-) HYPERBILIRUBINEMIC RATS

Chen¹,

Hennig²,

Manautou³

2003

Drug Metab Dispos

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ABSTRACT:The involvement of the canalicular multidrug resistance protein 2 (Mrp2) in the hepatobiliary excretion of acetaminophen (APAP)-glutathione (GSH) conjugate and its derivatives was investigated using transport-deficient (TR Acetaminophen (APAP 1 ) is biotransformed through phase I and phase II reactions into negatively charged, hydrophilic metabolites that are eliminated in urine and bile. Cytochrome P450 converts APAP to the highly reactive electrophile N-acetyl-p-benzoquinoneimine (Dahlin et al., 1984), which produces liver injury unless it is neutralized by conjugation with glutathione (GSH) (Mitchell et al., 1973). The resulting conjugate (APAP-GSH) can be sequentially metabolized to APAP-cysteinylglycine (APAP-CG), -cysteine (APAP-CYS), and -mercapturate (N-acetylated L-cysteine) (APAP-NAC). By contrast, conjugation with glucuronic acid and sulfate produces APAP-glucuronide (APAP-GLU) and APAP-sulfate (APAP-SUL), respectively. In several species, a large fraction of APAP-GSH undergoes biliary excretion in its original form and the rest is excreted in urine and bile as a mixture of thiol-containing derivatives, whereas the majority of APAP-GLU and APAP-SUL is excreted in urine (Gregus et al., 1988).Measuring the amount of APAP metabolites in urine and/or bile is considered a useful in vivo method for examining the effects of other chemicals on APAP metabolism, because changes in urinary and/or biliary excretion of APAP conjugates correlate well with changes in APAP biotransformation produced by xenobiotics (Jollow et al., 1974;Madhu et al., 1989;Liu et al., 1993). This approach assumes that membrane-associated transport systems for APAP metabolites in hepatocytes are not affected by xenobiotic treatment. With the recent identification and characterization of several apical and basolateral transporters (Muller and Jansen, 1997), it is now clear that the hepatic levels of some transport systems can be modulated by prototypical microsomal inducers such as pregnenolone 16␣-carbonitrile (Salphati and Benet, 1998), dexamethasone (Courtois et al., 1999), and phenobarbital (Ogawa et al., 2000). Therefore, these types of APAP disposition studies should be interpreted with respect to both xenobiotic inducibility of hepatic transporters and molecular mechanisms for the hepatic excretion of APAP and its metabolites.We recently showed that the biliary concentration of APAP-GSH, APAP-NAC, and APAP-GLU, but not that of APAP itself, APAP-SUL or APAP-CG/CYS, was significantly decreased by coadministration of the nonmetabolizable organic anion indocyanine green (ICG) in male CD-1 mice (Chen et al., 2000). These findings suggest that several APAP conjugates share hepatobiliary transport systems with ICG.A primary active transporter on the canalicular domain of hepatocytes, known as multidrug resistance protein 2 (Mrp2), mediates the hepatobiliary transport of a wide range of organic anions, including GSH-S-conjugates (e.g., leukotriene C4 and 2,4-dinitrophenyl-S-GSH), oxidized GSH (GSSG), glucuronide conjugates (e.g., ...

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“…In contrast to human hepatocytes, MRP2 mRNA expression in rat hepatocytes is markedly up-regulated by exposure to Dex. 12,[21][22][23][24] Therefore, the species differences observed in the present study and a previous study 12) indicate that the comparative study of the mRNA induction of transporters using primary cultures of cryopreserved human, cynomolgus monkey, and rat hepatocytes may be useful for evaluating candidate drugs in preclinical drug development.…”

Section: Fig 2 Effects Of Exposure To Drugs On Mdr1 Mrna Expressionmentioning

confidence: 48%

Comparison of Inducibility of Multidrug Resistance (MDR)1, Multidrug Resistance-Associated Protein (MRP)1, and MRP2 mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

Nishimura

Koeda²,

Morikawa³

et al. 2008

Biological & Pharmaceutical Bulletin

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Multidrug resistance 1 (MDR1, p-glycoprotein (P-gp), ABCB1) was the first human ATP binding cassette (ABC) transporter whose cDNA was cloned and characterized based on its ability to confer a multidrug-resistance phenotype to cancer cells. 1) Multidrug resistance-associated protein 1 (MRP1, ABCC1) and multidrug resistance-associated protein 2 (MRP2, ABCC2) have been identified as multidrug-resistance genes and demonstrated to transport glutathione conjugates of many toxic compounds.2,3) The tissue localization of MDR1 includes the choroid plexus (so-called bloodbrain barrier), adrenal gland, kidney, intestine, and liver; that of MRP1 is ubiquitous (but low in the liver); and that of MRP2 includes the kidney, intestine, and liver. [2][3][4] . Several in vivo studies have demonstrated that the expression of ABC transporters such as MDR1, MRP1, and MRP2 is up-or down-regulated by chemical compounds and nutrients in the rat 5,6) and mouse 7,8) liver. Several in vitro studies using human hepatocytes have demonstrated that the expression of ABC transporters such as MDR1 is up-regulated by microsomal enzyme inducers such as rifampicin (Rif) and dexamethasone (Dex).9,10) Furthermore, we have previously described a method for evaluating the mRNA induction of transporters following exposure to microsomal enzyme inducers and candidate drugs in primary cultures of human and rat hepatocytes.11,12) However, few studies have investigated the evaluation of MDR1, MRP1, and MRP2 mRNA expression in cynomolgus monkeys following exposure to drugs, although cynomolgus monkeys have commonly been employed in studies of drug metabolism and toxicity. Furthermore, evaluation employing cynomolgus monkeys as well as evaluation employing rats has been performed in numerous preclinical studies. In order to ensure that the results of preclinical studies involving evaluation by in vitro methods using primary cultures of hepatocytes are applicable to clinical studies, it is important to evaluate the information obtained by the primary culture of both human and cynomolgus monkey hepatocytes. The present study was therefore conducted to compare the inducibility of MDR1, MRP1, and MRP2 mRNAs following exposure to the prototypical microsomal enzyme inducers Rif, Dex, and omeprazole (Ome) in primary cultures of cryopreserved hepatocytes obtained from humans and cynomolgus monkeys. Research and Development Center, Otsuka Pharmaceutical Factory, Inc.; Japan: b Ina Research Inc.; Nishiminowa, Ina, Japan: c Ichikawa General Hospital; Ichikawa, Japan: and d Laboratory of Health Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University; Tsushima-naka, Okayama 700-8530, Japan. Received June 23, 2008; accepted September 8, 2008; published online September 8, 2008 This study investigated the changes in the mRNA levels of the ATP binding cassette (ABC) transporters multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and multidrug resistance-associated protein 2 (MRP2) following ex...

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Up‐regulation of multidrug resistance‐associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone

Cited by 100 publications

References 34 publications

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

HEPATOBILIARY EXCRETION OF ACETAMINOPHEN GLUTATHIONE CONJUGATE AND ITS DERIVATIVES IN TRANSPORT-DEFICIENT (TR^-) HYPERBILIRUBINEMIC RATS

Comparison of Inducibility of Multidrug Resistance (MDR)1, Multidrug Resistance-Associated Protein (MRP)1, and MRP2 mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

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Up‐regulation of multidrug resistance‐associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone

Cited by 100 publications

References 34 publications

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

HEPATOBILIARY EXCRETION OF ACETAMINOPHEN GLUTATHIONE CONJUGATE AND ITS DERIVATIVES IN TRANSPORT-DEFICIENT (TR-) HYPERBILIRUBINEMIC RATS

Comparison of Inducibility of Multidrug Resistance (MDR)1, Multidrug Resistance-Associated Protein (MRP)1, and MRP2 mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

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HEPATOBILIARY EXCRETION OF ACETAMINOPHEN GLUTATHIONE CONJUGATE AND ITS DERIVATIVES IN TRANSPORT-DEFICIENT (TR^-) HYPERBILIRUBINEMIC RATS