Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver

Hitzl, Monika; Klein, Kathrin; Zanger, Ulrich M.; Fritz, Péter; Nüssler, Andreas K.; Neuhaus, P.; Fromm, Martin F.

doi:10.1124/jpet.102.043547

Cited by 47 publications

(42 citation statements)

References 32 publications

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“…However, under long term stress conditions, e.g. during cholestasis, MRP3-dependent conjugate export provides an important rescue mechanism for the hepatocytes, based on the relatively slow process of up-regulation of MRP3 expression (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…In this case several compounds, normally extruded into the bile, are transported by MRP3 into the sinusoidal blood. MRP3 is also up-regulated under cholestatic conditions and agents (23)(24)(25). Thus the co-regulated function of MRP2 and MRP3 may have a major effect on the conjugate metabolism and bile acid secretion in the human liver.…”

mentioning

confidence: 89%

“…Estrogen metabolites and other steroid glucuronides show hepatotoxic effects (30) and mutually protect against cholestasis (31). In pregnancy and in hormone replacement therapy, taurocholate decreases E 2 17␤G uptake in isolated rat hepatocytes (32), and certain MRP3 substrates induce MRP3 overexpression in cholestatic conditions (23)(24)(25). All of these data suggest an interrelated transport of bile acids and glucuronide-conjugated metabolites in the liver cells.…”

mentioning

confidence: 92%

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Differential Modulation of the Human Liver Conjugate Transporters MRP2 and MRP3 by Bile Acids and Organic Anions

Bodó

Bakos

Szeri

et al. 2003

Journal of Biological Chemistry

145

117

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The multidrug resistance proteins MRP2 (ABCC2) and MRP3 (ABCC3) are key primary active transporters involved in anionic conjugate and drug extrusion from the human liver. The major physiological role of MRP2 is to transport conjugated metabolites into the bile canaliculus, whereas MRP3 is localized in the basolateral membrane of the hepatocytes and transports similar metabolites back to the bloodstream. Both proteins were shown to interact with a large variety of transported substrates, and earlier studies suggested that MRPs may work as co-transporters for different molecules. In the present study we expressed the human MRP2 and MRP3 proteins in insect cells and examined their transport and ATPase characteristics in isolated, inside-out membrane vesicles. We found that the primary active transport of estradiol-17-␤-D-glucuronide (E 2 17␤G), a major product of human steroid metabolism, was differently modulated by bile acids and organic anions in the case of human MRP2 and MRP3. Active E 2 17␤G transport by MRP2 was significantly stimulated by the organic anions indomethacin, furosemide, and probenecid and by several conjugated bile acids. In contrast, all of these agents inhibited E 2 17␤G transport by MRP3. We found that in the case of MRP2, ATP-dependent vesicular bile acid transport was increased by E 2 17␤G, and the results indicated an allosteric cross-stimulation, probably a cotransport of bile acids and glucuronate conjugates through this protein. There was no such stimulation of bile acid transport by MRP3. In conclusion, the different transport modulation of MRPs by bile acids and anionic drugs could play a major role in regulating physiological and pathological metabolite fluxes in the human liver.The homologous multidrug resistance ABC 1 transporter proteins MRP2 and MRP3 seem to be key players in the transport of organic anionic conjugated compounds in the liver and kidney (1-7). Unlike the selective "classical" transport proteins, multidrug transporters recognize and handle a wide range of substrates. The members of the MRP family are transporting hydrophobic anionic conjugates but may also extrude hydrophobic uncharged drugs. In this latter case drug transport by MRPs has been shown to be linked to the co-transport or allosteric effect of cellular reduced glutathione, GSH (2, 3, 6 -12).MRP2 in polarized cells is localized in the apical (luminal) membrane surface, predominantly in the canalicular membrane of hepatocytes but also in the apical membranes of kidney-proximal tubules (1-3, 6, 13). In contrast, MRP3 expression in polarized cells is restricted to the basolateral membrane (4). The lack of functional MRP2 causes the human disease Dubin-Johnson syndrome, which is associated with a large increase of conjugated bilirubin and other conjugated metabolites in the bloodstream. Several animal models are available for modeling this disease condition (14, 15), and there are known mutations/polymorphisms, reducing human MRP2 activity and leading to disorders of conjugate metabolism (16 -18).Liver cell...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

mentioning

confidence: 92%

See 1 more Smart Citation

Differential Modulation of the Human Liver Conjugate Transporters MRP2 and MRP3 by Bile Acids and Organic Anions

Bodó

Bakos

Szeri

et al. 2003

Journal of Biological Chemistry

145

117

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“…33,34 Resected tissue samples were morphologically examined by a pathologist, and only histologically normal liver tissue was used for further studies. The tissue samples were stored at À801C before subsequent processing.…”

Section: Dna and Liver Samplesmentioning

confidence: 99%

“…34 One or 2 mg of the isolated RNA were reverse-transcribed using the TaqMan Reverse Transcription Reagents (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. Real-time quantitative PCR was performed with the ABI PRISM 7700 Sequence Detection System (Applied Biosystems) by utilizing the 5 0 -nuclease assay with TaqMan probes.…”

Section: Blood Biochemistrymentioning

confidence: 99%

Variability in human hepatic MRP4 expression: influence of cholestasis and genotype

et al. 2007

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The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38-and 45-fold variability, respectively. We sequenced 2 kb of the 5 0 -flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 2997138 vs 100760a.u., Po0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.

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The molecular mechanism underlying the induction of hepatic MRP3 expression and function by omeprazole

Pan

et al. 2015

Biopharm & Drug Disp

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Previous work has indicated that there is increased protein expression of multidrug resistance-associated protein 3 (MRP3) in the liver samples of patients treated with omeprazole compared with those who were not. However, evidence is still lacking to show the mechanisms underlying that induction. This study aimed to assess changes in the fold-induction of MRP3 mRNA and protein expression over controls in omeprazole-treated HepG2 cells after transient transfection of human MRP3 siRNA, or after pretreatment with actinomycin D (Act-D). Furthermore, MRP3 siRNA knock-down or MRP-specific inhibition (indomethacin) was used to determine whether the MRP3 protein induced by omeprazole possessed an enhanced efflux transport. The results demonstrated that omeprazole induced MRP3 mRNA and protein expression in a concentration- and time-dependent manner. Moreover, that induction was almost completely abolished by the addition of human MRP3 siRNA and also by pretreatment with Act-D, respectively. In addition, the decay rate of MRP3 mRNA in vehicle- and omeprazole-treated cells was similar in the presence of Act-D, suggesting transcriptional up-regulation of MRP3 mRNA expression by omeprazole. Most importantly, omeprazole induced MRP3 efflux transport activity, as measured by the 5-carboxyfluorescein assay in the absence and presence of human MRP3 siRNA or indomethacin. It is concluded that omeprazole can induce MRP3 mRNA and protein expression and enhance MRP3 efflux transport activity through transcriptional up-regulation, and that omeprazole can also induce other MRP transporters.

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Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver

Cited by 47 publications

References 32 publications

Differential Modulation of the Human Liver Conjugate Transporters MRP2 and MRP3 by Bile Acids and Organic Anions

Differential Modulation of the Human Liver Conjugate Transporters MRP2 and MRP3 by Bile Acids and Organic Anions

Variability in human hepatic MRP4 expression: influence of cholestasis and genotype

The molecular mechanism underlying the induction of hepatic MRP3 expression and function by omeprazole

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