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Effect of organic anions and taurolithocholate-3-sulfate on biliary excretion of temocapril in the rat
Hepatology Research 15 (1999) 157 – 162
Effect of organic anions and taurolithocholate-3-sulfate on biliary excretion of temocapril in the rat Hajime Takikawa *, Naoyo Sano, Chiharu Suzuki, Yukiko Takada, Masami Yamanaka Department of Medicine, Teikyo Uni6ersity School of Medicine, Kaga 2 -11 -1, Itabashi-ku, Tokyo 173 -0003, Japan Received 2 February 1999; received in revised form 29 March 1999; accepted 6 April 1999
Abstract Biliary organic anion excretion is mediated by an ATP-dependent primary active transporter, canalicular multispecific organic anion transporter/multidrug resistance protein 2. On the other hand, a multiplicity of canalicular organic anion transporter has been suggested. To examine the substrate specificity of canalicular multispecific organic anion transporter, we examined the effect of organic anions and lithocholate-3-sulfate on biliary excretion of temocapril, a prodrug of an angiotensin-converting enzyme inhibitor, temocaprilat, in rats. Biliary excretion of temocapril was delayed in EHBR. Biliary excretion of temocapril was inhibited by sulfobromophthalein and taurolichocholate-3-sulfate, but was not inhibited by phenolphthalein glucuronide. These findings further support the multiplicity of canalicular organic anion transporter, and in spite of a glucuronide conjugate phenolphthalein glucuronide seems too hydrophobic to be a good substrate of canalicular multispecific organic anion transporter. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bile acid sulfate; Canalicular multispecific organic anion transporter/multidrug resistance protein 2; Eisai hyperbilirubinemic rats; Organic anions; Temocapril
* Corresponding author. Tel.: +81-3-3964-1211; fax: +81-3-3964-8477. E-mail address: [email protected] (H. Takikawa) 1386-6346/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 3 8 6 - 6 3 4 6 ( 9 9 ) 0 0 0 2 5 - X
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H. Takikawa et al. / Hepatology Research 15 (1999) 157–162
1. Introduction Biliary excretion of organic anions has been shown to be mediated by an ATP-dependent primary active transporter, canalicular multispecific organic anion transporter (cMOAT)/multidrug resistance protein 2 (mrp2), which is defective in mutant hyperbilirubinemic rats, TR − /GY rats and Eisai hyperbilirubinemic rats (EHBR) [1 – 3]. Recently, cDNA cloning of cMOAT has been reported and abnormalities of cMOAT mRNA in TR − /GY rats, EHBR and patients with Dubin – Johnson syndrome have been identified [4–9]. However, recent studies elucidated a multiplicity of canalicular organic anion transport, suggesting the existence of pathways other than through cMOAT for biliary organic anion excretion [10–20]. Temocapril is a prodrug of an angiotensin-converting enzyme inhibitor, temocaprilat, which is reported to be a substrate of cMOAT [21]. In the present study, to further understand the function and the multiplicity of canalicular transport of organic anions and bile acid conjugates, we examined the effects of organic anions and taurolithocholate-3-sulfate (3-sul-LC-tau) on biliary excretion of temocapril.
2. Methods Sulfobromophthalein (BSP) was purchased from Dai-ichi (Tokyo) and phenolphthalein glucuronide (PhG) from Sigma (St. Louis, MO, USA). 3-Sul-LC-tau was purchased from Sigma. [14C]Temocapril (18 mCi/mmol) was kindly provided by Sankyo Pharmaceutical (Tokyo, Japan). The other reagents were of analytical grade. Male Sprague – Dawley rats (SDR) were purchased from Japan Laboratory Animals (Saitama, Japan). EHBR were obtained from Sankyo Labo Service (Tokyo, Japan). All experiments were performed using rats each weighing approximately 270 g after overnight fasting. The rats were anesthetized with an intraperitoneal injection of pentobarbital (5 mg/100 g body wt.), and the common bile duct was cannulated with a PE-10 tube (Beckon-Dickinson Primary Care Diagnostics, Sparks, MD, USA) after laparotomy. The femoral vein was cannulated with a 3-Fr venous catheter, and 3% human albumin in 5% glucose solution (standard solution) was infused at the rate of 2 ml/h during the experiment. During the experiments, the rats were kept in restrictive cages and body temperature was maintained 37°C. Thirty minutes after bile duct cannulation, a tracer dose (2.2× 105 dpm) of 14 [ C]temocapril dissolved in 50 ml of the standard solution were injected via the femoral vein in SDR and EHBR. The infusion via the femoral vein of BSP, PhG, and 3-sul-LC-tau at the rate of 0.2 mmol/min per 100 g body wt. was started just after bile duct cannulation and continued during the experiments in SDR. Bile samples were collected every 10 min for 90 min in preweighed tubes, and counted for radioactivity by a liquid scintillation counter. Biliary excretion of temocapril was expressed as percent dose/10 min (the percentage of the administered radioactivity excreted in 10 min).
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All data were expressed as means 9SD. A statistical analysis was performed by the Mann – Whitney U-test, and PB 0.05 was considered to indicate a significant difference.
3. Results Biliary excretion of temocapril was markedly delayed in EHBR; cumulative excretion during 90 min was 10.2 9 0.8% in EHBR, compared with 46.09 4.9% in control rats (P B 0.05) (Fig. 1). Bile flow in EHBR was about 50% of control rats as reported previously [7]. BSP decreased biliary excretion of temocapril in SDR (cumulative excretion during 90 min was 17.89 3.0%, P B0.05 vs. control) (Fig. 2). In contrast, PhG did not inhibit biliary excretion of temocapril in SDR (cumulative excretion during 90 min was 35.3 94.8) (Fig. 3). Bile flow was not affected by the infusion of BSP and PhG in SDR. 3-Sul-LC-tau decreased biliary excretion of temocapril in SDR (cumulative excretion during 90 min was 12.191.0%, PB 0.05 vs. control) without changing bile flow (Fig. 4).
4. Discussion Biliary excretion of temocapril, which is excreted as temocaprilat in the bile, was markedly delayed in EHBR (Fig. 1) as has been reported by Ishizuka et al. [21].
Fig. 1. Biliary excretion of temocapril in SDR and EHBR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein. Data are the means 9 SD of SDR (n = 4, open circles) and EHBR (n= 3, closed circles).
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Fig. 2. Effect of BSP on biliary excretion of temocapril in SDR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein, and BSP was infused at the rate of 0.2 mmol/min per 100 g body wt. Data are the means9SD for control rats (n = 4, open circles) and experiments with BSP (n=3, closed circles).
The infusion of BSP and 3-sul-LC-tau inhibited biliary excretion of temocaprilat, although the extent of inhibition was not so prominent as its excretion in EHBR. In contrast, PhG did not inhibit the biliary excretion of temocapril, suggesting that PhG seems to be too hydrophilic to be a good substrate for cMOAT, as has been reported with ursodeoxycholate-3,7-disulfate [22–24]. These findings further indicate the existence of other excretory pathways of organic anions and bile acid
Fig. 3. Effect of PhG on biliary excretion of temocapril in SDR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein, and PhG was infused at the rate of 0.2 mmol/min per 100 g body wt. Data are the means9SD for control rats (n = 4, open circles) and experiments with PhG (n= 5, closed circles).
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Fig. 4. Effect of 3-sul-LC-tau on biliary excretion of temocapril in SDR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein, and 3-sul-LC-tau was infused at the rate of 0.2 mmol/min per 100 g body wt., respectively. Data are the means 9SD for control rats (n = 4, open circles) and experiments with 3-sul-LC-tau (n = 4, closed circles).
conjugates other than cMOAT. Indeed, recent studies elucidated the existence of other ATP-dependent organic anion transporters similar to cMOAT in the liver [25– 28]. However, the localization of these transporters in the liver is not fully understood. Further study is needed to clarify which transporters are localized at the canalicular membrane and have a role in biliary excretion of organic anions.
References [1] Jansen PL, Peters WH, Lamers WH. Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 1985;5:573 – 9. [2] Kuipers F, Enserink M, Havinga R, et al. Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat. J Clin Invest 1988;81:1593 – 9. [3] Takikawa H, Sano N, Narita R, et al. Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague–Dawley rats. Hepatology 1991;14:352 – 60. [4] Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y. Expression of a putative ATP-binding cassette region, homologous to that in multidrug resistance-associated protein (MRP), is hereditarily defective in Eisai hyperbilirubinemic rats (EHBR). Int Hepatol Commun 1996;4:291 – 8. [5] Paulusma CC, Bosma PJ, Zaman GJ, et al. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 1996;271:1126 – 8. [6] Buchler M, Konig J, Brom M, et al. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pomp deficient in hyperbilirubinemic mutant rats. J Biol Chem 1996;271:15091– 8. [7] Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y. Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 1997;272:G16 – 22. [8] Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin – Johnson syndrome. Hepatology 1997;25:1539 – 42.
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[9] Wada M, Toh S, Taniguchi K, et al. Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin–Johnson syndrome. Hum Mol Genet 1998;7:203 – 7. [10] Shimamura H, Suzuki H, Hanano M, et al. Multiple systems for the biliary excretion of organic anions in rats: Liquiritigenin conjugates as model compounds. J Pharmacol Exp Ther 1994;271:370–8. [11] Takikawa H, Nishikawa K, Sano N, Yamanaka M, Horie T. Mechanisms of biliary excretion of lithocholate-3-sulfate in Eisai hyperbilirubinemic rats (EHBR). Dig Dis Sci 1995;40:1792 – 7. [12] Takenaka O, Horie T, Suzuki H, Sugiyama Y. Different biliary excretion systems for glucuronide and sulfate of a model compound; study using Eisai hyperbilirubinemic rats. J Pharmacol Exp Ther 1995;274:1362–9. [13] Shimamura H, Suzuki H, Tagaya O, Horie T, Sugiyama Y. Biliary excretion of glycyrrhizin in rats: kinetic basis for multiplicity in bile canalicular transport of organic anions. Pharm Res 1996;13:1833–7. [14] Takikawa H, Yamazaki R, Sano N, Yamanaka M. Biliary excretion of estradiol-17b-glucuronide in the rat. Hepatology 1996;23:607–13. [15] Takikawa H, Sano N, Tadokoro K, Yamanaka M. Biliary excretion of estrone metabolites in the rat. Int Hepatol Commun 1996;5:251 – 8. [16] Takikawa H, Sano N, Uegaki S, Yamanaka M. Effects of bile acid conjugates on biliary excretion of estradiol-17b-glucuronide in the rat. Hepatol Res 1997;7:28 – 34. [17] Takikawa H, Sano N, Sato A, Yamanaka M. Effect of taurolithocholate-3-sulphate on biliary excretion of sulphobromophthalein and dibromosulphophthalein in the Eisai hyperbilirubinemic rat. J Gastroenterol Hepatol 1997;12:528 – 31. [18] Niinuma K, Takenaka O, Horie T, et al. Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-dinitrophenyl)-glutathione and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole glucuronide. J Pharmacol Exp Ther 1997;282:866 – 72. [19] Takikawa H, Sano N, Akimoto K, Yamanaka M. Biliary excretion of estrone sulfate in the rat. Hepatol Res 1998;11:201–7. [20] Sasabe H, Tsuji A, Sugiyama Y. Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats. J Pharmacol Exp Ther 1998;284:1033–9. [21] Ishizuka H, Konno K, Naganuma H, et al. Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic rats (EHBR). J Pharmacol Exp Ther 1997;280:1304 – 11. [22] Kitaura K, Takikawa H, Yamanaka M. Effects of organic anions and bile acid conjugates on biliary excretion of LTC4 in the rat. Prostaglandins 1997;54:745 – 55. [23] Fukumura S, Takikawa H, Yamanaka M. Effects of organic anions and bile acid conjugates on biliary excretion of pravastatin in the rat. Pharm Res 1998;15:72 – 6. [24] Takikawa H, Sano N, Ogasawara T, Yamanaka M. Enhanced biliary excretion of lithocholate-3sulfate by ursodeoxycholate-3,7-disulfate infusion in Eisai hyperbilirubinemic rat (EHBR). Dig Dis Sci 1998;43:188–92. [25] Hirohashi T, Suzuki H, Ito K, et al. Hepatic expression of multidrug-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats. Mol Pharmacol 1998;53:1068 – 75. [26] Kiuchi Y, Suzuki H, Hirohashi T, Tyson CA, Sugiyama Y. cDNA cloning and inducible expression of human multi-drug-resistance associated protein 3 (MRP3). FEBS Lett 1998;433:149 – 52. [27] Uchiumi T, Hinoshita E, Haga S, et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT 2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998;252:103 – 10. [28] Belinsky MG, Bain LJ, Balsara BB, Testa JR, Kruh GD. Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins. J Natl Cancer Inst 1998;90:1735–41. .
Effect of organic anions and taurolithocholate-3-sulfate on biliary excretion of temocapril in the rat Hajime Takikawa *, Naoyo Sano, Chiharu Suzuki, Yukiko Takada, Masami Yamanaka Department of Medicine, Teikyo Uni6ersity School of Medicine, Kaga 2 -11 -1, Itabashi-ku, Tokyo 173 -0003, Japan Received 2 February 1999; received in revised form 29 March 1999; accepted 6 April 1999
Abstract Biliary organic anion excretion is mediated by an ATP-dependent primary active transporter, canalicular multispecific organic anion transporter/multidrug resistance protein 2. On the other hand, a multiplicity of canalicular organic anion transporter has been suggested. To examine the substrate specificity of canalicular multispecific organic anion transporter, we examined the effect of organic anions and lithocholate-3-sulfate on biliary excretion of temocapril, a prodrug of an angiotensin-converting enzyme inhibitor, temocaprilat, in rats. Biliary excretion of temocapril was delayed in EHBR. Biliary excretion of temocapril was inhibited by sulfobromophthalein and taurolichocholate-3-sulfate, but was not inhibited by phenolphthalein glucuronide. These findings further support the multiplicity of canalicular organic anion transporter, and in spite of a glucuronide conjugate phenolphthalein glucuronide seems too hydrophobic to be a good substrate of canalicular multispecific organic anion transporter. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bile acid sulfate; Canalicular multispecific organic anion transporter/multidrug resistance protein 2; Eisai hyperbilirubinemic rats; Organic anions; Temocapril
* Corresponding author. Tel.: +81-3-3964-1211; fax: +81-3-3964-8477. E-mail address: [email protected] (H. Takikawa) 1386-6346/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 3 8 6 - 6 3 4 6 ( 9 9 ) 0 0 0 2 5 - X
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H. Takikawa et al. / Hepatology Research 15 (1999) 157–162
1. Introduction Biliary excretion of organic anions has been shown to be mediated by an ATP-dependent primary active transporter, canalicular multispecific organic anion transporter (cMOAT)/multidrug resistance protein 2 (mrp2), which is defective in mutant hyperbilirubinemic rats, TR − /GY rats and Eisai hyperbilirubinemic rats (EHBR) [1 – 3]. Recently, cDNA cloning of cMOAT has been reported and abnormalities of cMOAT mRNA in TR − /GY rats, EHBR and patients with Dubin – Johnson syndrome have been identified [4–9]. However, recent studies elucidated a multiplicity of canalicular organic anion transport, suggesting the existence of pathways other than through cMOAT for biliary organic anion excretion [10–20]. Temocapril is a prodrug of an angiotensin-converting enzyme inhibitor, temocaprilat, which is reported to be a substrate of cMOAT [21]. In the present study, to further understand the function and the multiplicity of canalicular transport of organic anions and bile acid conjugates, we examined the effects of organic anions and taurolithocholate-3-sulfate (3-sul-LC-tau) on biliary excretion of temocapril.
2. Methods Sulfobromophthalein (BSP) was purchased from Dai-ichi (Tokyo) and phenolphthalein glucuronide (PhG) from Sigma (St. Louis, MO, USA). 3-Sul-LC-tau was purchased from Sigma. [14C]Temocapril (18 mCi/mmol) was kindly provided by Sankyo Pharmaceutical (Tokyo, Japan). The other reagents were of analytical grade. Male Sprague – Dawley rats (SDR) were purchased from Japan Laboratory Animals (Saitama, Japan). EHBR were obtained from Sankyo Labo Service (Tokyo, Japan). All experiments were performed using rats each weighing approximately 270 g after overnight fasting. The rats were anesthetized with an intraperitoneal injection of pentobarbital (5 mg/100 g body wt.), and the common bile duct was cannulated with a PE-10 tube (Beckon-Dickinson Primary Care Diagnostics, Sparks, MD, USA) after laparotomy. The femoral vein was cannulated with a 3-Fr venous catheter, and 3% human albumin in 5% glucose solution (standard solution) was infused at the rate of 2 ml/h during the experiment. During the experiments, the rats were kept in restrictive cages and body temperature was maintained 37°C. Thirty minutes after bile duct cannulation, a tracer dose (2.2× 105 dpm) of 14 [ C]temocapril dissolved in 50 ml of the standard solution were injected via the femoral vein in SDR and EHBR. The infusion via the femoral vein of BSP, PhG, and 3-sul-LC-tau at the rate of 0.2 mmol/min per 100 g body wt. was started just after bile duct cannulation and continued during the experiments in SDR. Bile samples were collected every 10 min for 90 min in preweighed tubes, and counted for radioactivity by a liquid scintillation counter. Biliary excretion of temocapril was expressed as percent dose/10 min (the percentage of the administered radioactivity excreted in 10 min).
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All data were expressed as means 9SD. A statistical analysis was performed by the Mann – Whitney U-test, and PB 0.05 was considered to indicate a significant difference.
3. Results Biliary excretion of temocapril was markedly delayed in EHBR; cumulative excretion during 90 min was 10.2 9 0.8% in EHBR, compared with 46.09 4.9% in control rats (P B 0.05) (Fig. 1). Bile flow in EHBR was about 50% of control rats as reported previously [7]. BSP decreased biliary excretion of temocapril in SDR (cumulative excretion during 90 min was 17.89 3.0%, P B0.05 vs. control) (Fig. 2). In contrast, PhG did not inhibit biliary excretion of temocapril in SDR (cumulative excretion during 90 min was 35.3 94.8) (Fig. 3). Bile flow was not affected by the infusion of BSP and PhG in SDR. 3-Sul-LC-tau decreased biliary excretion of temocapril in SDR (cumulative excretion during 90 min was 12.191.0%, PB 0.05 vs. control) without changing bile flow (Fig. 4).
4. Discussion Biliary excretion of temocapril, which is excreted as temocaprilat in the bile, was markedly delayed in EHBR (Fig. 1) as has been reported by Ishizuka et al. [21].
Fig. 1. Biliary excretion of temocapril in SDR and EHBR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein. Data are the means 9 SD of SDR (n = 4, open circles) and EHBR (n= 3, closed circles).
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Fig. 2. Effect of BSP on biliary excretion of temocapril in SDR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein, and BSP was infused at the rate of 0.2 mmol/min per 100 g body wt. Data are the means9SD for control rats (n = 4, open circles) and experiments with BSP (n=3, closed circles).
The infusion of BSP and 3-sul-LC-tau inhibited biliary excretion of temocaprilat, although the extent of inhibition was not so prominent as its excretion in EHBR. In contrast, PhG did not inhibit the biliary excretion of temocapril, suggesting that PhG seems to be too hydrophilic to be a good substrate for cMOAT, as has been reported with ursodeoxycholate-3,7-disulfate [22–24]. These findings further indicate the existence of other excretory pathways of organic anions and bile acid
Fig. 3. Effect of PhG on biliary excretion of temocapril in SDR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein, and PhG was infused at the rate of 0.2 mmol/min per 100 g body wt. Data are the means9SD for control rats (n = 4, open circles) and experiments with PhG (n= 5, closed circles).
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Fig. 4. Effect of 3-sul-LC-tau on biliary excretion of temocapril in SDR. A tracer amount of radiolabeled temocapril was injected as a bolus into the femoral vein, and 3-sul-LC-tau was infused at the rate of 0.2 mmol/min per 100 g body wt., respectively. Data are the means 9SD for control rats (n = 4, open circles) and experiments with 3-sul-LC-tau (n = 4, closed circles).
conjugates other than cMOAT. Indeed, recent studies elucidated the existence of other ATP-dependent organic anion transporters similar to cMOAT in the liver [25– 28]. However, the localization of these transporters in the liver is not fully understood. Further study is needed to clarify which transporters are localized at the canalicular membrane and have a role in biliary excretion of organic anions.
References [1] Jansen PL, Peters WH, Lamers WH. Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 1985;5:573 – 9. [2] Kuipers F, Enserink M, Havinga R, et al. Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat. J Clin Invest 1988;81:1593 – 9. [3] Takikawa H, Sano N, Narita R, et al. Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague–Dawley rats. Hepatology 1991;14:352 – 60. [4] Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y. Expression of a putative ATP-binding cassette region, homologous to that in multidrug resistance-associated protein (MRP), is hereditarily defective in Eisai hyperbilirubinemic rats (EHBR). Int Hepatol Commun 1996;4:291 – 8. [5] Paulusma CC, Bosma PJ, Zaman GJ, et al. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 1996;271:1126 – 8. [6] Buchler M, Konig J, Brom M, et al. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pomp deficient in hyperbilirubinemic mutant rats. J Biol Chem 1996;271:15091– 8. [7] Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y. Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 1997;272:G16 – 22. [8] Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin – Johnson syndrome. Hepatology 1997;25:1539 – 42.
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[9] Wada M, Toh S, Taniguchi K, et al. Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin–Johnson syndrome. Hum Mol Genet 1998;7:203 – 7. [10] Shimamura H, Suzuki H, Hanano M, et al. Multiple systems for the biliary excretion of organic anions in rats: Liquiritigenin conjugates as model compounds. J Pharmacol Exp Ther 1994;271:370–8. [11] Takikawa H, Nishikawa K, Sano N, Yamanaka M, Horie T. Mechanisms of biliary excretion of lithocholate-3-sulfate in Eisai hyperbilirubinemic rats (EHBR). Dig Dis Sci 1995;40:1792 – 7. [12] Takenaka O, Horie T, Suzuki H, Sugiyama Y. Different biliary excretion systems for glucuronide and sulfate of a model compound; study using Eisai hyperbilirubinemic rats. J Pharmacol Exp Ther 1995;274:1362–9. [13] Shimamura H, Suzuki H, Tagaya O, Horie T, Sugiyama Y. Biliary excretion of glycyrrhizin in rats: kinetic basis for multiplicity in bile canalicular transport of organic anions. Pharm Res 1996;13:1833–7. [14] Takikawa H, Yamazaki R, Sano N, Yamanaka M. Biliary excretion of estradiol-17b-glucuronide in the rat. Hepatology 1996;23:607–13. [15] Takikawa H, Sano N, Tadokoro K, Yamanaka M. Biliary excretion of estrone metabolites in the rat. Int Hepatol Commun 1996;5:251 – 8. [16] Takikawa H, Sano N, Uegaki S, Yamanaka M. Effects of bile acid conjugates on biliary excretion of estradiol-17b-glucuronide in the rat. Hepatol Res 1997;7:28 – 34. [17] Takikawa H, Sano N, Sato A, Yamanaka M. Effect of taurolithocholate-3-sulphate on biliary excretion of sulphobromophthalein and dibromosulphophthalein in the Eisai hyperbilirubinemic rat. J Gastroenterol Hepatol 1997;12:528 – 31. [18] Niinuma K, Takenaka O, Horie T, et al. Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-dinitrophenyl)-glutathione and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole glucuronide. J Pharmacol Exp Ther 1997;282:866 – 72. [19] Takikawa H, Sano N, Akimoto K, Yamanaka M. Biliary excretion of estrone sulfate in the rat. Hepatol Res 1998;11:201–7. [20] Sasabe H, Tsuji A, Sugiyama Y. Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats. J Pharmacol Exp Ther 1998;284:1033–9. [21] Ishizuka H, Konno K, Naganuma H, et al. Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic rats (EHBR). J Pharmacol Exp Ther 1997;280:1304 – 11. [22] Kitaura K, Takikawa H, Yamanaka M. Effects of organic anions and bile acid conjugates on biliary excretion of LTC4 in the rat. Prostaglandins 1997;54:745 – 55. [23] Fukumura S, Takikawa H, Yamanaka M. Effects of organic anions and bile acid conjugates on biliary excretion of pravastatin in the rat. Pharm Res 1998;15:72 – 6. [24] Takikawa H, Sano N, Ogasawara T, Yamanaka M. Enhanced biliary excretion of lithocholate-3sulfate by ursodeoxycholate-3,7-disulfate infusion in Eisai hyperbilirubinemic rat (EHBR). Dig Dis Sci 1998;43:188–92. [25] Hirohashi T, Suzuki H, Ito K, et al. Hepatic expression of multidrug-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats. Mol Pharmacol 1998;53:1068 – 75. [26] Kiuchi Y, Suzuki H, Hirohashi T, Tyson CA, Sugiyama Y. cDNA cloning and inducible expression of human multi-drug-resistance associated protein 3 (MRP3). FEBS Lett 1998;433:149 – 52. [27] Uchiumi T, Hinoshita E, Haga S, et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT 2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998;252:103 – 10. [28] Belinsky MG, Bain LJ, Balsara BB, Testa JR, Kruh GD. Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins. J Natl Cancer Inst 1998;90:1735–41. .