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Kouzuki, Hirokazu; Suzuki, Hiroshi; Sugiyama, Yuichi

doi:10.1023/a:1007576903935

Cited by 40 publications

(16 citation statements)

References 21 publications

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“…The competitive inhibitory effect of IDM on the BSP transport also should be considered because Oatp1b2 and Mrp2 are also responsible for the biliary excretion of IDM and its glucuronide. 29,30) However, a pilot study showed that it seemed to be minor because a coadministration of IDM (1.0 mg/kg) at 2 h prior to BSP injection affected neither its plasma elimination nor biliary excretion (data not shown). The reduction in the mRNA levels of Oatp1b2 and Mrp2 was similar to that in their protein levels (Fig.…”

Section: Discussionmentioning

confidence: 98%

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: 98%

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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“…The effect of co-transfection with an expression construct for the Na ϩ -taurocholate co-transporting polypeptide was also determined. Na ϩ -taurocholate co-transporting polypeptide is found on the basolateral membrane of hepatocytes, and is the major protein responsible for transporting bile acids from the blood into the liver, and exhibits affinity for both conjugated and unconjugated bile acids (31,32). As shown in Fig.…”

Section: Cloning and Expression Of Murine Mrp3mentioning

confidence: 99%

Vitamin D Receptor-dependent Regulation of Colon Multidrug Resistance-associated Protein 3 Gene Expression by Bile Acids

McCarthy

Sinal

2005

Journal of Biological Chemistry

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“…A recent in vivo investigation of three drugs, considered MRP2 substrates by in vitro studies, found that EHBR mutant rats had negligible capacity for biliary export of two of the drugs, probenecid and methotrexate, but they had a comparable biliary output of the third, furosemide [18]. Dominant roles for MRP2 were demonstrated for biliary export of the glucuronide metabolites of the nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac and indomethacin, whereas minor or no apparent roles were found for the parent compounds of the NSAIDs indomethacin and sulindac [19][20][21]. Delays in the biliary output of glucuronide and sulfate metabolites of the type II diabetes drug trogliatazone were observed Consequences of MRP2 Deficiency 233 in TR À rats, which is consistent with transport by a compensatory lowaffinity biliary exporter, once metabolites have accumulated within hepatocytes [22].…”

Section: Influence Of Mrp2-deficiency On Biliary Export Of Endogenousmentioning

confidence: 99%

“…Based on observations in MRP2-deficient rats, biliary secretion of the acyl glucuronide metabolites of two NSAIDs, diclofenac and indomethacin, occurs predominantly via the MRP2 exporter. For indomethacin, a 2-fold decrease in its glucuronide metabolite was measured in bile collected following drug treatment of MRP2-deficient rats as compared with bile from wild-type rats [20]. For diclofenac, there appears to be a more dramatic impact as only trace levels of its glucuronide metabolites were recovered in bile of MRP2-deficient rats as compared with recovery of >50% of the dose administered in wild-type rats [21,38].…”

Section: Altered Responses Of Mrp2-deficient Rats To Nsaidsmentioning

confidence: 99%

Consequences of MRP2 Deficiency: Lessons from Rats with a Mutation in This Exporter

Treinen-Moslen

Kaphalia

Kanz

2003

Comments on Toxicology

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Abstract: These results indicate that another transporter(s) is involved in the hepatic uptake of indomethacin and the canalicular transport of indomethacin glucuronide is mediated by cMOAT/MRP2 whereas that of indomethacin is not mediated by cMOAT/MRP2.

Cited by 40 publications

References 21 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

Vitamin D Receptor-dependent Regulation of Colon Multidrug Resistance-associated Protein 3 Gene Expression by Bile Acids

Consequences of MRP2 Deficiency: Lessons from Rats with a Mutation in This Exporter

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