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Background & Aims
Multid
rug
resistance-associated p
rotein 2 (in hu
mans, MRP2; in
rodents, M
rp2)
mediates bilia
ry exc
retion of bili
rubin glucu
ronides. The
refo
re, up
regulation of MRP2/M
rp2 exp
ression
may i
mp
rove hype
rbili
rubine
mia. We investigated the effects of 4-phenylbuty
rate (4PBA), a d
rug used to t
reat o
rnithine t
ransca
rba
mylase deficiency (OTCD), on the cell su
rface exp
ression and t
ranspo
rt function of MRP2/M
rp2 and se
ru
m T-Bil concent
ration.
Methods
MRP2-expressing MDCKII (MRP2-MDCKII) cells and rats were studied to explore the change induced by 4PBA treatment in the cell surface expression and transport function of MRP2/Mrp2 and its underlying mechanism. Serum and liver specimens from OTCD patients were analyzed to examine the effect of 4PBA on hepatic MRP2 expression and serum T-Bil concentration in humans.
Results
In MRP2-MDCKII cells and the rat liver, 4PBA increased the cell surface expression and transport function of MRP2/Mrp2. In patients with OTCD, hepatic MRP2 expression increased and serum T-Bil concentration decreased significantly after 4PBA treatment. m>In vitrom> studies designed to explore the mechanism underlying this drug action suggested that cell surface-resident MRP2/Mrp2 is degraded via ubiquitination-mediated targeting to the endosomal/lysosomal degradation pathway and that 4PBA inhibits the degradation of cell surface-resident MRP2/Mrp2 by reducing its susceptibility to ubiquitination.
Conclusions
4PBA activates MRP2/Mrp2 function through increased expression of MRP2/Mrp2 at the hepatocanalicular membrane by modulating its ubiquitination, and thereby decreases serum T-Bil concentration. 4PBA has thus therapeutic potential for improving hyperbilirubinemia.