Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

Mahdi, Zainab Mustafa; Synal-Hermanns, U.; Yoker, Aylin; Locher, Kaspar P.; Stieger, Bruno

doi:10.1124/mol.116.103390

Cited by 40 publications

(29 citation statements)

References 78 publications

(94 reference statements)

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“…Initially, we used stably expressed human hepatocyte transporters, which we had originally cloned and localized, namely, OATP1B3 (formerly OATP8) for uptake and MRP2 (ABCC2) for efflux, to investigate transcellular transport in polarized MDCKII cells [8] . Additional transporter combinations and substrates were subsequently published by Yuichi Sugiyama's group in Tokyo [9,60] , many other laboratories [61][62][63] , as well as by our own group in Heidelberg [28,43,[64][65][66] . These double-transfected polarized cells have clearly established that both uptake and efflux transport proteins are necessary to obtain the manifold increase in the rate of transcellular transport comparable to the transporter interaction and transport efficiency observed in the intact liver [8,10] .…”

Section: Insights From Polarized Cells Stably Expressing Recombinant mentioning

confidence: 99%

Progress in the Molecular Characterization of Hepatobiliary Transporters

Keppler

2017

Dig Dis

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Over the last 25 years, our understanding of the driving forces for hepatobiliary elimination and knowledge of the molecular basis of uptake and efflux transport in hepatocytes have undergone fundamental changes. This refers to bile acids and many other endogenous substances as well as to drugs that are eliminated on the hepatobiliary route. In this development, not only molecular cloning, functional characterization, and localization of transporters were decisive, but also the discovery of hereditary mutations in genes encoding sinusoidal uptake transporters and canalicular export pumps in humans and rodents. Uptake by passive diffusion and elimination into bile driven by the electrochemical gradient are no longer considered relevant for hepatobiliary elimination in the intact organism. Furthermore, insights into the relative roles of uptake transporters and unidirectional ATP-driven efflux pumps were obtained when we established double-transfected polarized cell lines stably expressing, as an example, the hepatocellular uptake transporter OATP1B3 and the apical (canalicular) efflux pump multidrug resistance protein 2 (MRP2; ABCC2). ATP-dependent efflux transporters localized to the basolateral (sinusoidal) hepatocyte membrane, particularly MRP3 (ABCC3) and MRP4 (ABCC4), pump substances from hepatocytes into sinusoidal blood. Bile acids are substrates for human MRP4 in the presence of physiological concentrations of reduced glutathione, which undergoes co-transport. These efflux pumps have been recognized in recent years to play an important compensatory role in cholestasis and to contribute to the balance between uptake and efflux of bile acids and other organic anions during the vectorial transport from blood into bile. This sinusoidal efflux not only enables subsequent renal elimination but also facilitates the re-uptake of substances into neighboring hepatocytes located more centrally and downstream in the sinusoid.

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Section: Insights From Polarized Cells Stably Expressing Recombinant mentioning

confidence: 99%

Progress in the Molecular Characterization of Hepatobiliary Transporters

Keppler

2017

Dig Dis

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“…Cefuroxime does not inhibit BSEP, MRP2 or MRP3, but causes an intermediate inhibition of MRP4 and as shown here has not effect on MDR3 (Figure ). Although amoxicillin/clavulanic acid is the most common drug associated with DILI, there is no inhibition of MDR3 activity . Furthermore, amoxicillin does not inhibit any of the transporters and clavulanic acid does not inhibit BSEP …”

Section: Discussionmentioning

confidence: 99%

“…In order to obtain more information on the role of BSEP and MDR3 in the pathogenesis of the cholestatic episodes, the interaction of the antibiotic cefuroxime with these two canalicular ABC‐transporters using a newly established assay system has been studied. Figure shows that the activities of MDR3 and BSEP were not affected by up to 100 μM cefuroxime.…”

Section: Case Reportmentioning

confidence: 99%

A rare cause of a cholestatic jaundice in a North African teenager

Schreiner

Stieger

Mclin³

et al. 2019

Liver International

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We report an unusual case of intermittent episodes of cholestasis in a young patient. The cholestatic attacks were preceded in each case by an infection and subsequent antibiotic therapies. After ruling out many possible causes of cholestatic hepatitis, the differential diagnoses were a benign recurrent intrahepatic cholestasis or a drug‐induced liver injury. We discuss here the diagnostic approach and interpretation of the genetic analysis.

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“…61 As canalicular lipid secretion requires the interaction of 3 different ABC transporters, 12 a polar LLC-PK1 cell line stably expressing BSEP, MDR3, and ABCG5/ABCG8 at the apical membrane and NTCP at the basolateral membrane was established. 62 Using this cell line for modeling canalicular lipid secretion, itraconazole was found to inhibit the secretion of the fluorescent PC derivative 1-palmitoyl-2-{6-[(7-nitro-2-1,3-bonzoxadiazol-4-yl)amino]hex-anoyl}-sn-glycero-3-phosphocholine (C 6 -NBD-PC) by 42% at 10 mM.…”

Section: Role Of Mdr3 In Drug-induced Cholestasismentioning

confidence: 99%

“…In both studies, an interference of itraconazole (and other drugs tested) on the biosynthesis of PC cannot entirely be ruled out. Mahdi et al 62 tested the impact of itraconazole on MDR3-mediated secretion of the fluorescent PC C 6 -NBD-PC under a basolateral to apical, that is, transcellular flux of taurocholate, which mimics the physiological situation in hepatocytes and with albumin in the apical compartment as phospholipid acceptor. To the best of our knowledge, currently, no data on the affinity (K m ) of PC or C6-NBD-PC to MDR3 are available.…”

Section: Role Of Mdr3 In Drug-induced Cholestasismentioning

confidence: 99%

Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease

Stieger

Mahdi

2017

Journal of Pharmaceutical Sciences

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Bile formation is a key function of the liver. Disturbance of bile flow may lead to liver disease and is called cholestasis. Cholestasis may be inherited, for example, in progressive familial intrahepatic cholestasis or acquired, for example, by drug-mediated inhibition of bile salt export from hepatocytes into the canaliculi. The key transport system for exporting bile salts into the canaliculi is the bile salt export pump. Inhibition of the bile salt export pump by drugs is a well-established cause of drug-induced cholestasis. Investigation of the role of the multidrug resistance protein 3, essential for biliary phospholipid secretion, is emerging now. This overview summarizes current concepts and methods with an emphasis on in vitro model systems for the investigation of drug-induced cholestasis in the general context of drug-induced liver injury.

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Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

Cited by 40 publications

References 78 publications

Progress in the Molecular Characterization of Hepatobiliary Transporters

Progress in the Molecular Characterization of Hepatobiliary Transporters

A rare cause of a cholestatic jaundice in a North African teenager

Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease

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