Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides.
Glucuronidation is a major hepatic detoxification pathway for endogenous and exogenous compounds, resulting in the intracellular formation of polar metabolites that require specialized transporters for elimination. Multidrug resistance proteins (MRPs) are expressed in the liver and can transport glucuronosyl-conjugates. Using morphine as a model aglycone, we demonstrate that morphine-3-glucuronide (M3G), the predominant metabolite, is transported in vitro by human MRP2 (ABCC2), a protein present in the apical membrane of hepatocytes. Loss of biliary M3G secretion in Mrp2(-/-) mice results in its increased sinusoidal transport that can be attributed to Mrp3. Combined loss of Mrp2 and Mrp3 leads to a substantial accumulation of M3G in the liver, from which it is transported across the sinusoidal membrane at a low rate, resulting in the prolonged presence of M3G in plasma. Our results show that murine Mrp2 and Mrp3 provide alternative routes for the excretion of a glucuronidated substrate from the liver in vivo.
van de Wetering
Koen
K
Division of Molecular Biology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Zelcer
Noam
N
Kuil
Annemieke
A
Feddema
Wouter
W
Hillebrand
Michel
M
Vlaming
Maria L H
ML
Schinkel
Alfred H
AH
Beijnen
Jos H
JH
Borst
Piet
P
D000818:Animals; D002460:Cell Line; D014453:Glucuronosyltransferase / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D009022:Morphine Derivatives / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D018411:Spodoptera
D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D009022:Morphine Derivatives; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3; C491474:UGT2B7 protein, human; C018108:morphine-3-glucuronide