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Received for publication January 25, 2006.
Revised June 29, 2006.
Accepted for publication July 18, 2006.
The hepatic excretion of hydrophilic conjugates, endproducts of phase II metabolism, is not completely understood. In the present studies, transport mechanism(s) responsible for the biliary excretion of 4-methylumbelliferyl glucuronide (4MUG) and 4-methylumbelliferyl sulfate (4MUS) were studied. Isolated perfused livers (IPLs) from Mrp2-deficient (TR-) Wistar rats, were used to examine the role of Mrp2 in the biliary excretion of 4MUG and 4MUS. Following a 30-µmol dose of 4-methylumbelliferone, cumulative biliary excretion of 4MUG was extensive in wild-type rat IPLs (25 ± 3 µmol), but was negligible in TR- livers (0.4 ± 0.1 µmol); co-administration of the Bcrp and P-glycoprotein inhibitor, GF120918, had no effect on 4MUG biliary excretion in wild-type rat IPLs. In contrast, biliary excretion of 4MUS was partially maintained in Mrp2-deficient rat IPLs. Recovery of 4MUS in bile was ~50-60% lower in both control TR- (149 ± 8 nmol) and wild-type IPLs with GF120918 co-administration (176 ± 30 nmol) relative to wild-type control livers (378 ± 37 nmol), and was nearly abolished in TR- IPLs in the presence of GF120918 (13 ± 8 nmol). These changes were the result of decreased rate constants governing 4MUG and 4MUS biliary excretion. In vitro assays and perfused livers from Bcrp and P-glycoprotein gene-knockout mice indicated that 4MUS did not interact with P-glycoprotein, but was transported by Bcrp in a GF120918-sensitive manner. In the rat liver, Mrp2 mediates the biliary excretion of 4MUG, whereas both Mrp2 and Bcrp contribute almost equally to the transport of 4MUS into bile.
Key words:
4-methylumbelliferone, Bcrp, Mrp2, glucuronide, liver, sulfate
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