TY - JOUR
T1 - Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2
AU - Hirsova, Petra
AU - Karlasova, Gabriela
AU - Dolezelova, Eva
AU - Cermanova, Jolana
AU - Zagorova, Marie
AU - Kadova, Zuzana
AU - Hroch, Milos
AU - Sispera, Ludek
AU - Tomsik, Pavel
AU - Lenicek, Martin
AU - Vitek, Libor
AU - Pavek, Petr
AU - Kucera, Otto
AU - Cervinkova, Zuzana
AU - Micuda, Stanislav
N1 - Funding Information:
The authors thank Hana Lastuvkova and Jitka Hajkova for excellent technical assistance and Katerina Sildbergerova and Dagmar Jezkova for care of animals. We gratefully thank to Dr. Makoto Makishima, Nihon University School of Medicine, Japan, for pCMX-GAL4-FXR construct. We would like to acknowledge Dr. James L. Boyer and colleagues associated with his lab and the Yale Liver Center for their expertise in hepatocyte sandwich cultures and valuable intellectual contributions to this study. This work was supported by Charles University , grants nos. 132309 , P37/05 (PRVOUK), and SVV-2012-264901 and partly supported by Czech Scientific Agency , grant no. P303/12/G136 .
PY - 2013/1/7
Y1 - 2013/1/7
N2 - Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of EGCG on bile flow and bile acid homeostasis in rats. Compared to controls, EGCG treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. EGCG administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by EGCG. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, EGCG markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When EGCG was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of EGCG to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions EGCG may induce cholestasis.
AB - Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of EGCG on bile flow and bile acid homeostasis in rats. Compared to controls, EGCG treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. EGCG administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by EGCG. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, EGCG markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When EGCG was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of EGCG to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions EGCG may induce cholestasis.
KW - Bile acids
KW - Bile formation
KW - Cholestasis
KW - Epigallocatechin gallate
UR - http://www.scopus.com/inward/record.url?scp=84870490561&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870490561&partnerID=8YFLogxK
U2 - 10.1016/j.tox.2012.10.018
DO - 10.1016/j.tox.2012.10.018
M3 - Article
C2 - 23146761
AN - SCOPUS:84870490561
SN - 0300-483X
VL - 303
SP - 9
EP - 15
JO - Toxicology
JF - Toxicology
ER -