RT Journal Article
SR Electronic
T1 Multidrug Resistance Proteins 2 and 3 Provide Alternative Routes for Hepatic Excretion of Morphine-Glucuronides
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 387
OP 394
DO 10.1124/mol.107.035592
VO 72
IS 2
A1 Koen van de Wetering
A1 Noam Zelcer
A1 Annemieke Kuil
A1 Wouter Feddema
A1 Michel Hillebrand
A1 Maria L. H. Vlaming
A1 Alfred H. Schinkel
A1 Jos H. Beijnen
A1 Piet Borst
YR 2007
UL http://molpharm.aspetjournals.org/content/72/2/387.abstract
AB 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.