Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2

Kamisako, Toshinori; Leier, Inka; Cui, Yunhai; König, Jörg; Buchholz, Ulrike; Hummel‐Eisenbeiss, Johanna; Keppler, Dietrich

doi:10.1002/hep.510300220

Cited by 169 publications

(105 citation statements)

References 38 publications

(80 reference statements)

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“…As for rMrp2, the free liver concentration of rifampicin did not reach the IC 50 value of Mrp2 (34.0 mM), which was obtained using CDCF as a typical substrate for rMrp2. Although CDCF was used as a substrate for rMrp2 in the present study, the reported IC 50 value of cyclosporin A using bilirubin monoglucuronide as an rMrp2 substrate (Kamisako et al, 1999) was almost consistent with our determined IC 50 value of cyclosporin A. In addition, inhibition studies of rifampicin for rNtcp, rBsep, and rUgt1a1 were conducted but the inhibitory effects were low.…”

Section: Biomarkers For Inhibition Of Transporterssupporting

confidence: 83%

“…In hepatobiliary transporters, bilirubins are substrates of OATPs (Cui et al, 2001;Briz et al, 2003) and MRP2 (Kamisako et al, 1999), whereas bile acids are substrates of NTCP (Hagenbuch and Meier, 1994;Stieger, 2011) and BSEP (Noé et al, 2002;Stieger, 2011). Therefore, when the transporters are inhibited by exogenous substances such as drugs, it appears that plasma levels of bilirubins or bile acids are increased independently of drug-induced hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Watanabe¹,

Miyake²,

Shimizu³

et al. 2015

Drug Metab Dispos

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It is useful to identify endogenous substrates for the evaluation of drug-drug interactions via transporters. In this study, we investigated the utility of bilirubins, substrates of OATPs and MRP2, and bile acids and substrates of NTCP and BSEP, as biomarkers for the inhibition of transporters. In rats administered 20 and 80 mg/kg rifampicin, the plasma levels of bilirubin glucuronides were elevated, gradually decreased, and almost returned to the baseline level at 24 hours after administration without an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This result indicates the transient inhibition of rOatps and/or rMrp2. Although the correlation between free plasma concentrations and IC 50 values of rOatps depended on the substrates used in the in vitro studies, the inhibition of rOatps by rifampicin was confirmed in the in vivo study using valsartan as a substrate of rOatps. In rats administered 10 and 30 mg/kg cyclosporin A, the plasma levels of bile acids were elevated and persisted for up to 24 hours after administration without an elevation of ALT and AST. This result indicates the continuous inhibition of rNtcp and/or rBsep, although there were differences between the free plasma or liver concentrations and IC 50 values of rNtcp or rBsep, respectively. This study suggests that the monitoring of bilirubins and bile acids in plasma is useful in evaluating the inhibitory potential of their corresponding transporters.

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Section: Biomarkers For Inhibition Of Transporterssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Watanabe¹,

Miyake²,

Shimizu³

et al. 2015

Drug Metab Dispos

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“…26 MRP2 mRNA levels appeared lower in PFIC livers (Table 3), but the differences did not reach significance because of considerable variation in MRP2 mRNA and protein levels (Fig. 4B).…”

Section: Resultsmentioning

confidence: 92%

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

et al. 2005

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Mutations of the bile salt export pump (BSEP) or the multidrug resistance P-glycoprotein 3 (MDR3) are linked to impaired bile salt homeostasis and lead to progressive familial intrahepatic cholestasis (PFIC)-2 and -3, respectively. The regulation of bile salt transporters in PFIC is not known. Expression of hepatobiliary transporters in livers of ten patients with a PFIC phenotype was studied by quantitative reverse transcription polymerase chain reaction, Western blotting, and immunofluorescence microscopy. PFIC was diagnosed by clinical and laboratory findings. All patients could be assigned to PFIC-2 or PFIC-3 by the use of BSEP-and MDR3-specific antibodies and by MDR3 gene-sequencing. Whereas in all PFIC-2 patients, BSEP immunoreactivity was absent from the canalicular membrane, in three PFIC-3 livers, canalicular MDR3 immunoreactivity was detectable. Serum bile salts were elevated to 276 ؎ 233 and to 221 ؎ 109 mol/L in PFIC-2 and PFIC-3, respectively. Organic anion transporting polypeptide OATP1B1, OATP1B3, and MRP2 mRNA and protein levels were reduced, whereas sodium taurocholate cotransporting polypeptide (NTCP) was only reduced at the protein level, suggesting a posttranscriptional NTCP regulation. Whereas MRP3 mRNA and protein were not significantly altered, MRP4 messenger RNA and protein were significantly increased in PFIC. In conclusion, PFIC-2 may be reliably diagnosed by immunofluorescence, whereas the diagnosis of PFIC-3 requires gene-sequencing. Several mechanisms may contribute to elevated plasma bile salts in PFIC: reduced bile salt uptake via NTCP, OATP1B1, and OATP1B3, decreased BSEP-dependent secretion into bile, and increased transport back into plasma by MRP4. Upregulation of MRP4, but not of MRP3, might represent an important escape mechanism for bile salt extrusion in PFIC. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/ suppmat/index.html). (HEPATOLOGY 2005;41:1160-1172

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“…The molecular and biochemical aspects, and clinical relevance of these transporters have been well-described in recent reviews. [146][147][148][149][150][151][152][153][154] It has been demonstrated that certain drugs are substrates for these transporters, e.g., digoxin, paclitaxel and vinblastine for MDR3 155) ; bilirubin conjugates for MRP2 156) ; anticancer drugs, and glucronide and GSH conjugates for MRP3 [157][158][159] ; cidfovir and adefovir for OAT1 160) ; methotrexate and cimetidine for OAT3 161) ; pravastatin 162,163) and methotrexate 164,165) for OATP-C (OATP2, LST-1); digoxin for OATP8 166) ; quinidine (at pH 6.0) for OCT1 167) ; amantadine for OCT2 168) ; quinidine and verapamil for OCTN1 169) ; and quinidine and verapamil for OCTN2. 170,171) It has been established that genetic polymorphisms of drug metabolizing enzymes are responsible for inter-individual differences of pharmacokinetics and thereby pharmacodynamics, however, little is known about the effects of genetic polymorphisms of membrane transporters.…”

Section: Polymorphisms Of Other Transportersmentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

169

110

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The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

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Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2

Cited by 169 publications

References 38 publications

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

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