New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition.
BACKGROUND
For the elimination of environmental chemicals and metabolic waste products, the body is equipped with a range of broad specificity transporters that are present in excretory organs as well as in several epithelial blood-tissue barriers.


METHODS
ABCC2 and ABCC3 (also known as MRP2 and MRP3) mediate the transport of various conjugated organic anions, including many drugs, toxicants and endogenous compounds. This review focuses on the physiology of these transporters, their roles in drug disposition and how they affect drug sensitivity and toxicity. It also examines how ABCC2 and ABCC3 are coordinately regulated at the transcriptional level by members of the nuclear receptor (NR) family of ligand-modulated transcription factors and how this can be therapeutically exploited.


CONCLUSIONS
Mutations in both ABCC2 and ABCC3 have been associated with changes in drug disposition, sensitivity and toxicity. A defect in ABCC2 is associated with Dubin-Johnson syndrome, a recessively inherited disorder characterized by conjugated hyperbilirubinemia. Pharmacological manipulation of the activity of these transporters can potentially improve the pharmacokinetics and thus therapeutic activity of substrate drugs but also affect the physiological function of these transporters and consequently ameliorate associated disease states.
University of Groningen, University Medical Center Groningen, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics , Hanzeplein 1, 9713 GZ Groningen , The Netherlands j.w.jonker@umcg.nl.
Lori W E
LW
van der Schoor
Henkjan J
HJ
Verkade
Folkert
F
Kuipers
Johan W
JW
Jonker
D000818:Animals; D001692:Biological Transport; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D004364:Pharmaceutical Preparations; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3
ABC transporters; cholestasis hepatobiliary transport; hyperbilirubinemia; nuclear receptors