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Rapid CommunicationSpecial Section on Transporters in Toxicity and Disease

The Roles of MRP2, MRP3, OATP1B1, and OATP1B3 in Conjugated Hyperbilirubinemia

Dietrich Keppler
Drug Metabolism and Disposition April 2014, 42 (4) 561-565; DOI: https://doi.org/10.1124/dmd.113.055772
Dietrich Keppler
German Cancer Research Center (DKFZ), Heidelberg, Germany
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Abstract

Increased concentrations of bilirubin glucuronides in blood plasma indicate hepatocellular dysfunction. Elucidation of the transport processes of bilirubin conjugates across the basolateral (sinusoidal) and the canalicular plasma membrane domains of hepatocytes has decisively contributed to our current understanding of the molecular basis of conjugated hyperbilirubinemia in human liver diseases. Under normal conditions, unconjugated bilirubin is taken up into hepatocytes by transporters of the organic anion–transporting polypeptide (OATP) family, followed by conjugation with glucuronic acid, and ATP-dependent transport into bile. This efflux across the canalicular membrane is mediated by multidrug resistance protein 2 (MRP2 or ABCC2), which is a 190-kDa glycoprotein transporting with high affinity and efficiency monoglucuronosyl bilirubin and bisglucuronosyl bilirubin into bile. MRP2 is hereditarily deficient in human Dubin-Johnson syndrome. Under pathophysiological conditions such as cholestatic liver injury and MRP2 inhibition, the basolateral efflux pump multidrug resistance protein 3 (MRP3 or ABCC3) is responsible for the occurrence of conjugated hyperbilirubinemia. MRP3 is a glycoprotein with a similar molecular mass as MRP2, with 48% amino acid identity, and with overlapping substrate specificity. Human MRP3 is the only basolateral efflux pump shown to transport bilirubin glucuronides. In human and rat hepatocytes, MRP3/Mrp3 is strongly upregulated under conditions of cholestasis and MRP2 deficiency. This is in line with the concept that basolateral efflux pumps of the hepatocyte compensate for impaired canalicular efflux of compounds into bile and contribute to balance the rate of uptake or synthesis of compounds in hepatocytes with the capacity for efflux into bile.

Footnotes

    • Received November 3, 2013.
    • Accepted January 23, 2014.
  • dx.doi.org/10.1124/dmd.113.055772.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Rapid CommunicationSpecial Section on Transporters in Toxicity and Disease

MRP2, MRP3, and OATPs in Conjugated Hyperbilirubinemia

Dietrich Keppler
Drug Metabolism and Disposition April 1, 2014, 42 (4) 561-565; DOI: https://doi.org/10.1124/dmd.113.055772

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Rapid CommunicationSpecial Section on Transporters in Toxicity and Disease

MRP2, MRP3, and OATPs in Conjugated Hyperbilirubinemia

Dietrich Keppler
Drug Metabolism and Disposition April 1, 2014, 42 (4) 561-565; DOI: https://doi.org/10.1124/dmd.113.055772
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  • Article
    • Abstract
    • MRP2 and MRP3 Are Conjugate and Drug Efflux Pumps of the Multidrug Resistance Protein (ATP-Binding Cassette Protein, Subfamily C) Subfamily of ATP-Dependent Transport Proteins
    • Transport of Unconjugated Bilirubin into Human Hepatocytes
    • Transport of Conjugated Bilirubin by Human Hepatocytes
    • Predominantly Conjugated Hyperbilirubinemia in Rotor Syndrome
    • Predominantly Conjugated Hyperbilirubinemia in Dubin-Johnson Syndrome
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