Decreased Mrp2-dependent bile flow in the post-warm ischemic rat liver.
BACKGROUND
The link between microcirculatory disturbance and hepatocellular dysfunction remains unknown. The present study was designed to examine the key event of warm ischemia reperfusion (WIR) injury with subsequent cholestasis.


METHODS
A left lobar 70% ischemia and reperfusion rat model was used in this study. The portal vein and hepatic artery to the left lateral lobe of the liver were subjected to 20 min of warm ischemia followed by 60 min of reperfusion to collect bile and to measure its constituents.


RESULTS
The hepatocellular injury was increased significantly in livers exposed to WIR, as judged by serum alanine aminotransferase. This event coincided with decreased bile production and biliary concentration of glutathione (GSH), suggesting impaired bile salts-independent bile flow, while biliary phospholipids and bile salts were not decreased. Additionally, hepatic adenosine triphosphate and GSH were not decreased after WIR. Since the biliary GSH, which is a major driving force for bile salts-independent bile flow, is excreted from hepatocytes into the bile via multidrug resistance protein 2 (Mrp2), we examined whether intracellular localization of Mrp2 occurred. Immunohistochemical analyses revealed hepatocellular Mrp2 was retrieved from bile canalicular membrane into the pericanalicular cytoplasm in the post-warm ischemic livers. Microcirculatory disturbance in livers exposed to 20 min of warm ischemia improved to levels comparable to controls.


CONCLUSIONS
Mrp2 internalization, observed in this study, may play an important determinant of cholestasis in the post-warm ischemic livers.
Ban
Daisuke
D
Department of Hepatobiliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Kudo
Atsushi
A
Sui
Shaoguang
S
Tanaka
Shinji
S
Nakamura
Noriaki
N
Ito
Koji
K
Suematsu
Makoto
M
Arii
Shigeki
S
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000209:etiology*; D008099:Liver / Q000502:physiology*; D008297:Male; D008833:Microcirculation; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D015427:Reperfusion Injury / Q000150:complications*; D013997:Time Factors; D052096:Warm Ischemia / Q000009:adverse effects*
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat