Biliary excretion of tauroursodeoxycholate, ICG and BSP in bile duct-ligated rats
Various hepatic transporters such as Mrp 2 and Bsep are considered to be down-regulated in obstructive jaundice. In the present study, the biliary transport maximum (Tm) of tauroursodeoxycholate (TUDC), a Bsep substrate, BSP, an Mrp 2 substrate, and ICG was studied in bile ductligated rats for 3 day...
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| Published in | Tando Vol. 19; no. 1; pp. 28 - 32 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | Japanese |
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Japan Biliary Association
2005
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| ISSN | 0914-0077 1883-6879 |
| DOI | 10.11210/tando1987.19.1_28 |
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| Abstract | Various hepatic transporters such as Mrp 2 and Bsep are considered to be down-regulated in obstructive jaundice. In the present study, the biliary transport maximum (Tm) of tauroursodeoxycholate (TUDC), a Bsep substrate, BSP, an Mrp 2 substrate, and ICG was studied in bile ductligated rats for 3 days (BDL rats). In BDL rats, the Tm of TUDC and ICG was decreased to 53%and 40% of controls. The Tm of BSP was markedly decreased in BDL rats (13% of controls), and was relieved to 44% of controls by the coadministration of TUDC. The decrease of the Tm of TUDC was not as prominent as that of taurocholate, probably due to the enhancement of the vesicular targeting of Bsep to the canalicular membrane and the phosphorylation of Bsep, which are specific to TUDC. The recovery of the Tm of BSP by TUDC in BDL rats is considered to be due to the partial recovery of the Mrp 2 function by TUDC. |
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| AbstractList | Various hepatic transporters such as Mrp 2 and Bsep are considered to be down-regulated in obstructive jaundice. In the present study, the biliary transport maximum (Tm) of tauroursodeoxycholate (TUDC), a Bsep substrate, BSP, an Mrp 2 substrate, and ICG was studied in bile ductligated rats for 3 days (BDL rats). In BDL rats, the Tm of TUDC and ICG was decreased to 53%and 40% of controls. The Tm of BSP was markedly decreased in BDL rats (13% of controls), and was relieved to 44% of controls by the coadministration of TUDC. The decrease of the Tm of TUDC was not as prominent as that of taurocholate, probably due to the enhancement of the vesicular targeting of Bsep to the canalicular membrane and the phosphorylation of Bsep, which are specific to TUDC. The recovery of the Tm of BSP by TUDC in BDL rats is considered to be due to the partial recovery of the Mrp 2 function by TUDC.
閉塞性黄疸では, 各種肝トランスポーターが減少し, Mrp2やBsepの機能が低下すると考えられている.今回, 閉塞性黄疸時の肝指向性物質の胆汁中排泄の検討のため, Bsepの基質であるタウロウルソデオキシコール酸(TUDC)とMrp2の基質であるBSP, およびICGの胆汁中最大排泄量(Tm)を3日間の胆管結紮(BDL)ラットで検討した.TUDCおよびICGのTmはBDLラットで, それぞれ対照の53%と40%に低下した. BSPのTmはBDLラットで対照の13%に低下し, TUDC同時投与により44%まで改善した.TUDCのTmの減少は, Bsepの基質であるタウロコール酸ほど顕著でなく, TUDCに特異的なBsepの毛細胆管膜への小胞輸送の亢進のためと考えられた. TUDC同時投与によりBDLで低下したBSPのTmの改善は, TUDCによるMrp2機能の部分的回復によるものと考えられた. Various hepatic transporters such as Mrp 2 and Bsep are considered to be down-regulated in obstructive jaundice. In the present study, the biliary transport maximum (Tm) of tauroursodeoxycholate (TUDC), a Bsep substrate, BSP, an Mrp 2 substrate, and ICG was studied in bile ductligated rats for 3 days (BDL rats). In BDL rats, the Tm of TUDC and ICG was decreased to 53%and 40% of controls. The Tm of BSP was markedly decreased in BDL rats (13% of controls), and was relieved to 44% of controls by the coadministration of TUDC. The decrease of the Tm of TUDC was not as prominent as that of taurocholate, probably due to the enhancement of the vesicular targeting of Bsep to the canalicular membrane and the phosphorylation of Bsep, which are specific to TUDC. The recovery of the Tm of BSP by TUDC in BDL rats is considered to be due to the partial recovery of the Mrp 2 function by TUDC. |
| Author | TAKAMORI, Yoriyuki AKASHI, Masahiro TANAKA, Atsushi TAKIKAWA, Hajime MIKAMI, Masaki UEGAKI, Satoko SASAMOTO, Takahiro SANO, Naoyo NAGAMACHI, Yukiko TAKAYANAGI, Motoe KURIHARA, Hiroko |
| Author_FL | 上垣 佐登子 高森 頼雪 滝川 一 栗原 裕子 三神 昌樹 笹本 貴広 田中 篤 高柳 もとえ 明石 雅博 長町 由紀子 佐野 直代 |
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| References | 14) Kurz AK, Graf D, Schmitt M, vom Dahl S, Haussinger D. Taurodeoxycholate-iuduced ch o leresis involves P 381AP" activation and transloc a tion of the bile salt export pump. Gastroenterology 2001; 121: 407-19 3) Gerloff T, Stieger B, Hagenbuch B, et al. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 1998; 273: 10046-50 7) Trauner M, Arrese M, Soroka CJ, et al. The rat canalicular conjugate export pump (Mrp 2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 1997; 113: 255-64 18) Sathirakul K, Suzuki H, Yasuda K, et al. Kinetic analysis of hepatobiliary transport of o r ganic anions in Eisai hyperbilirubinemic mutant r ats. J Pharmacol Exp Ther 1993; 265: 1301-12 平成16年12月24日 15) Noe J, St-Pierre MV, Meier PJ. Function and regulation of expression of the canalicular bile salt. export pump. In: Paumgartner G, Keppler D, Le u schner U, et al, eds. Bile acids: from genomic s to disease and therapy. Dordrecht: Kluwer, 2003: 92-7 6) D umont M, Jacquemin E, D'hont C, et al. Expression of the liver Nat-independent organic anion transporting polypeptide (oatp-1) in rats with bile duct ligation. J Hepatol 1997; 27: 1051-6 8) Lee JM, Trauner M, Soroka CJ, Stieger B, Meier PJ, Boyer JL. Expression of the bile salt e x port pump is maintained after chronic cholestasis in the rat. Gastroenterology 2000; 118: 163-72 1) Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier PJ. Functional expression cloning and cha r acterization of the hepatocyte Na/bile a cid cotransporting system. Proc Natl Acad Sci U S A 1991; 88: 10629-33 12) Tachizawa H, Sano N, Takikawa H. Effects of colchicine on the maximum biliary excretion of cholephilic compounds in rats. J Gastroenterol Hepatol 2004; 19: 1016-22 4) Paulusma C C, Bosma PJ, Zaman GJ, et al. Congenital jaundice rats with a mutation in a m u ltidrug resistance-associated protein gene. Scienc e 1996; 271: 1126-8 17) Tsuboi K, Tazurna S, Ochi H, et al. Hydrophilic bile salts have a cytoprotective effect against cyclosporine A-induced cholestasis through e nhanced canalicular membrane fluidity and transp o rter activity. Hepatol Res 2003; 25: 38-47 2) Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ. Expression cloning of a r a t liver Na-independent organic anion transporter. Proc Natl Acad Sci USA 1994; 91: 133-7 19) Takikawa H, Sano N, Fukumura S, Uegaki S, Yamanaka M. Impaired biliary excretion of organic anions and cations in bile duct-ligated ra t. Int Hepatol Common 1996; 5: 201-6 20) Takikawa H, Sano N, Onishi T, et al. Biliary excretion of taurolithocholate-sulfate and temocaprilat in cholestatic rats induced by bile duct-1igation and ethinylestradiol. Hepatol Res 2002; 24: 136-40 10) Takikawa H, Wako Y, Sano N, Yamanaka M. Changes in biliary excretory mechanisms in the b i l e duct-ligated rat. Dig Dis Scli 1996; 41: 256-62 5) Gartun g C, Ananthanarayanan M, Rahman MA, et al. Down-regulation of expression and function o f the rat liver Nat/bile acid cotransporter in extrahe patic cholestasis. Gastroenterology 1996; 110: 199-209 13) Wakabayashi Y, Lippincott-Schwartz J, Arias IM. Intracellular trafficking of bile salt export pump (ABCB 11) in polarized hepatic cells: constitutive cycling between the canalicular mem b rane and rab 11-positive endosomes. Mol Biol Cell 200 4; 15: 3485-96 9) Paulusma CC, Kothe MJ, Bakker CT, et al. Zonal down-regulation and redistribution of the m ultidrug resistance protein 2 during bile duct ligati o n in rat liver. Hepatology 2000; 31: 684-93 11) Takikawa H, Sano N, Akimoto K, Ogasawara T, Yamanaka M. Effects of colchicine and phenoth i azine on biliary excretion of organic anions in rats. J Gastroenterol Hepatol 1998; 13: 427-32 16) Beuers U, Bilzer M, Chittattu A, et al. Tauroursodeoxycholic acid inserts the apical c o njugate export pump, Mrp 2, into canalicular m e m branes and stimulates organic anion secretion b y protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 2001; 33: 1206-16 |
| References_xml | – reference: 8) Lee JM, Trauner M, Soroka CJ, Stieger B, Meier PJ, Boyer JL. Expression of the bile salt e x port pump is maintained after chronic cholestasis in the rat. Gastroenterology 2000; 118: 163-72 – reference: 12) Tachizawa H, Sano N, Takikawa H. Effects of colchicine on the maximum biliary excretion of cholephilic compounds in rats. J Gastroenterol Hepatol 2004; 19: 1016-22 – reference: 1) Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier PJ. Functional expression cloning and cha r acterization of the hepatocyte Na/bile a cid cotransporting system. Proc Natl Acad Sci U S A 1991; 88: 10629-33 – reference: 11) Takikawa H, Sano N, Akimoto K, Ogasawara T, Yamanaka M. Effects of colchicine and phenoth i azine on biliary excretion of organic anions in rats. J Gastroenterol Hepatol 1998; 13: 427-32 – reference: 17) Tsuboi K, Tazurna S, Ochi H, et al. Hydrophilic bile salts have a cytoprotective effect against cyclosporine A-induced cholestasis through e nhanced canalicular membrane fluidity and transp o rter activity. Hepatol Res 2003; 25: 38-47 – reference: 20) Takikawa H, Sano N, Onishi T, et al. Biliary excretion of taurolithocholate-sulfate and temocaprilat in cholestatic rats induced by bile duct-1igation and ethinylestradiol. Hepatol Res 2002; 24: 136-40 – reference: 5) Gartun g C, Ananthanarayanan M, Rahman MA, et al. Down-regulation of expression and function o f the rat liver Nat/bile acid cotransporter in extrahe patic cholestasis. Gastroenterology 1996; 110: 199-209 – reference: 13) Wakabayashi Y, Lippincott-Schwartz J, Arias IM. Intracellular trafficking of bile salt export pump (ABCB 11) in polarized hepatic cells: constitutive cycling between the canalicular mem b rane and rab 11-positive endosomes. Mol Biol Cell 200 4; 15: 3485-96 – reference: 18) Sathirakul K, Suzuki H, Yasuda K, et al. Kinetic analysis of hepatobiliary transport of o r ganic anions in Eisai hyperbilirubinemic mutant r ats. J Pharmacol Exp Ther 1993; 265: 1301-12 – reference: 19) Takikawa H, Sano N, Fukumura S, Uegaki S, Yamanaka M. Impaired biliary excretion of organic anions and cations in bile duct-ligated ra t. Int Hepatol Common 1996; 5: 201-6 – reference: 10) Takikawa H, Wako Y, Sano N, Yamanaka M. Changes in biliary excretory mechanisms in the b i l e duct-ligated rat. Dig Dis Scli 1996; 41: 256-62 – reference: 2) Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ. Expression cloning of a r a t liver Na-independent organic anion transporter. Proc Natl Acad Sci USA 1994; 91: 133-7 – reference: 9) Paulusma CC, Kothe MJ, Bakker CT, et al. Zonal down-regulation and redistribution of the m ultidrug resistance protein 2 during bile duct ligati o n in rat liver. Hepatology 2000; 31: 684-93 – reference: 16) Beuers U, Bilzer M, Chittattu A, et al. Tauroursodeoxycholic acid inserts the apical c o njugate export pump, Mrp 2, into canalicular m e m branes and stimulates organic anion secretion b y protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 2001; 33: 1206-16 – reference: 平成16年12月24日 – reference: 4) Paulusma C C, Bosma PJ, Zaman GJ, et al. Congenital jaundice rats with a mutation in a m u ltidrug resistance-associated protein gene. Scienc e 1996; 271: 1126-8 – reference: 7) Trauner M, Arrese M, Soroka CJ, et al. The rat canalicular conjugate export pump (Mrp 2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 1997; 113: 255-64 – reference: 6) D umont M, Jacquemin E, D'hont C, et al. Expression of the liver Nat-independent organic anion transporting polypeptide (oatp-1) in rats with bile duct ligation. J Hepatol 1997; 27: 1051-6 – reference: 14) Kurz AK, Graf D, Schmitt M, vom Dahl S, Haussinger D. Taurodeoxycholate-iuduced ch o leresis involves P 381AP" activation and transloc a tion of the bile salt export pump. Gastroenterology 2001; 121: 407-19 – reference: 15) Noe J, St-Pierre MV, Meier PJ. Function and regulation of expression of the canalicular bile salt. export pump. In: Paumgartner G, Keppler D, Le u schner U, et al, eds. Bile acids: from genomic s to disease and therapy. Dordrecht: Kluwer, 2003: 92-7 – reference: 3) Gerloff T, Stieger B, Hagenbuch B, et al. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 1998; 273: 10046-50 |
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| Snippet | Various hepatic transporters such as Mrp 2 and Bsep are considered to be down-regulated in obstructive jaundice. In the present study, the biliary transport... |
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| SubjectTerms | Bile duct-ligated rat biliary excretion BSP ICG tauroursodeoxycholate タウロウルソデオキシコール酸 胆汁中排泄 胆管結紮ラット |
| Title | Biliary excretion of tauroursodeoxycholate, ICG and BSP in bile duct-ligated rats |
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