Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer.
OBJECTIVE
Hyperbilirubinemia is a critical complication following hepatectomy for biliary cancer. Hepatic multidrug resistance protein 2 (MRP2), a bilirubin transporter, is shown to be down-regulated by acute biliary obstruction in rats. However, little is known about the effect of chronic obstruction by malignancy on the MRP2 expression in patients or the association of MRP2 expression with posthepatectomy hyperbilirubinemia.


METHODS
The MRP2 expression before hepatectomy was determined by immunostaining and Western blotting in patients with biliary cancer. To directly determine the effect of chronic bile duct obstruction on the MRP2 expression, the expression levels were compared between the cholestatic and noncholestatic lobes in each of seven patients. In another 39 patients, the correlation of the MRP2 expression of the anticipated remnant liver with the posthepatectomy severe hyperbilirubinemia, defined as a serum total bilirubin concentration>or=200 micromol/l, was evaluated.


RESULTS
The MRP2 staining in the cholestatic lobes was weak and not restricted to the canalicular membrane, unlike the noncholestatic lobes. The expression levels in the cholestatic lobes were 45% of those in the noncholestatic lobes. Postoperative maximum bilirubin levels were significantly correlated with MRP2 expression of the anticipated remnant liver. The MRP2 expression had been already impaired before hepatectomy in all patients who eventually developed severe hyperbilirubinemia.


CONCLUSIONS
Decreased MRP2 expression, caused by biliary obstruction due to cancer, is a possible risk factor for posthepatectomy severe hyperbilirubinemia.
Yamada
Tatsuharu
T
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Arai
Toshiyuki
T
Nagino
Masato
M
Oda
Koji
K
Shoda
Junichi
J
Suzuki
Hiroshi
H
Sugiyama
Yuichi
Y
Nimura
Yuji
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001661:Biliary Tract Neoplasms / Q000601:surgery*; D002780:Cholestasis, Intrahepatic / Q000209:etiology / Q000378:metabolism / Q000601:surgery; D018432:Drug Resistance, Multiple; D005260:Female; D006498:Hepatectomy / Q000009:adverse effects*; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*
D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human