![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication December 27, 2004.
Revised March 23, 2005.
Accepted for publication March 29, 2005.
MRP3 is an ABC transporter that is able to confer resistance to anticancer agents such as etoposide and to transport lipophilic anions such as bile acids and glucuronides. These capabilities, along with the induction of MRP3 protein on hepatocyte sinusoidal membranes in cholestasis, and expression of MRP3 in enterocytes, have led to the hypotheses that MRP3 may function in the body to protect normal tissues from etoposide, to protect cholestatic hepatocytes from endobiotics and to facilitate bile acid reclamation from the gut. To elucidate the role of Mrp3 in these processes the Mrp3 gene (Abcc3) was disrupted by homologous recombination. Homozygous null animals were healthy and physically indistinguishable from wild-type mice. Mrp3-/- mice did not exhibit enhanced lethality to etoposide phosphate, although analysis of transfected HEK293 cells indicated that the potency of murine Mrp3 towards etoposide (~2.0-2.5-fold) is comparable to that of human MRP3. Following induction of cholestasis by bile duct ligation, Mrp3-/- mice had 1.5-fold higher levels of liver bile acids and 3.1-fold lower levels of serum bilirubin glucuronide compared to ligated wild-type mice, whereas significant differences were not observed between the respective sham-operated mice. Bile acid excretion, pool size and fractional turnover rates were similar in Mrp3-/- and wild-type mice. We conclude that Mrp3 functions as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes, that the pump does not play a major role in the enterohepatic circulation of bile acids, and that the lack of chemosensitivity is likely attributable to functional redundancy with other pumps.
Key words:
MDR/p-Glycoprotein, Organic anion, Liver transporters
This article has been cited by other articles:
|
|
 |
|
  M. Hirouchi, H. Kusuhara, R. Onuki, B. W. Ogilvie, A. Parkinson, and Y. Sugiyama Construction of Triple-Transfected Cells [Organic Anion-Transporting Polypeptide (OATP) 1B1/Multidrug Resistance-Associated Protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for Analysis of the Sinusoidal Function of MRP3 and MRP4 Drug Metab. Dispos., October 1, 2009; 37(10): 2103 - 2111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. L. Csanaky, L. M. Aleksunes, Y. Tanaka, and C. D. Klaassen Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice Am J Physiol Gastrointest Liver Physiol, September 1, 2009; 297(3): G419 - G433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. de Waart, M. L. H. Vlaming, C. Kunne, A. H. Schinkel, and R. P. J. O. Elferink Complex Pharmacokinetic Behavior of Ezetimibe Depends on Abcc2, Abcc3, and Abcg2 Drug Metab. Dispos., August 1, 2009; 37(8): 1698 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Alnouti Bile Acid Sulfation: A Pathway of Bile Acid Elimination and Detoxification Toxicol. Sci., April 1, 2009; 108(2): 225 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tanaka, L. M. Aleksunes, Y. J. Cui, and C. D. Klaassen ANIT-Induced Intrahepatic Cholestasis Alters Hepatobiliary Transporter Expression via Nrf2-Dependent and Independent Signaling Toxicol. Sci., April 1, 2009; 108(2): 247 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. L. Ernst, Y. Zhang, J. W. Yoo, S. J. Ernst, and J. L. Noebels Genetic Enhancement of Thalamocortical Network Activity by Elevating {alpha}1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy J. Neurosci., February 11, 2009; 29(6): 1615 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Hopper-Borge, X. Xu, T. Shen, Z. Shi, Z.-S. Chen, and G. D. Kruh Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B Cancer Res., January 1, 2009; 69(1): 178 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L.H. Vlaming, Z. Pala, A. van Esch, E. Wagenaar, O. van Tellingen, D. R. de Waart, R. P.J. Oude Elferink, K. van de Wetering, and A. H. Schinkel Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the In vivo Elimination of Methotrexate and its Main Toxic Metabolite 7-hydroxymethotrexate Clin. Cancer Res., December 15, 2008; 14(24): 8152 - 8160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Maher, L. M. Aleksunes, M. Z. Dieter, Y. Tanaka, J. M. Peters, J. E. Manautou, and C. D. Klaassen Nrf2- and PPAR{alpha}-Mediated Regulation of Hepatic Mrp Transporters after Exposure to Perfluorooctanoic Acid and Perfluorodecanoic Acid Toxicol. Sci., December 1, 2008; 106(2): 319 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kitamura, M. Hirouchi, H. Kusuhara, J. D. Schuetz, and Y. Sugiyama Increasing Systemic Exposure of Methotrexate by Active Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3) J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 465 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Okada, J. Shoda, K. Taguchi, J. M. Maher, K. Ishizaki, Y. Inoue, M. Ohtsuki, N. Goto, K. Takeda, H. Utsunomiya, et al. Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice Am J Physiol Gastrointest Liver Physiol, October 1, 2008; 295(4): G735 - G747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Tian, B. Swift, M. J. Zamek-Gliszczynski, M. G. Belinsky, G. D. Kruh, and K. L. R. Brouwer Impact of Basolateral Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 on the Hepatobiliary Disposition of Fexofenadine in Perfused Mouse Livers Drug Metab. Dispos., May 1, 2008; 36(5): 911 - 915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lu, S. Choudhuri, K. Ogura, I. L. Csanaky, X. Lei, X. Cheng, P.-z. Song, and C. D. Klaassen Characterization of Organic Anion Transporting Polypeptide 1b2-null Mice: Essential Role in Hepatic Uptake/Toxicity of Phalloidin and Microcystin-LR Toxicol. Sci., May 1, 2008; 103(1): 35 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rao, J. Haywood, A. L. Craddock, M. G. Belinsky, G. D. Kruh, and P. A. Dawson The organic solute transporter {alpha}-{beta}, Ost{alpha}-Ost{beta}, is essential for intestinal bile acid transport and homeostasis PNAS, March 11, 2008; 105(10): 3891 - 3896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. M. Villanueva, M. L. Ruiz, C. I. Ghanem, M. G. Luquita, V. A. Catania, and A. D. Mottino Hepatic Synthesis and Urinary Elimination of Acetaminophen Glucuronide Are Exacerbated in Bile Duct-Ligated Rats Drug Metab. Dispos., March 1, 2008; 36(3): 475 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Klaassen and H. Lu Xenobiotic Transporters: Ascribing Function from Gene Knockout and Mutation Studies Toxicol. Sci., February 1, 2008; 101(2): 186 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tanaka, C. Chen, J. M. Maher, and C. D. Klaassen Ischemia-Reperfusion of Rat Livers Decreases Liver and Increases Kidney Multidrug Resistance Associated Protein 2 (Mrp2) Toxicol. Sci., January 1, 2008; 101(1): 171 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tarmalinggam and E. S. Prakash How Does Conjugated Bilirubin Appear in the Bloodstream? Advan Physiol Educ, December 1, 2007; 31(4): 370 - 371. [Full Text] [PDF]
|
|
|
|
|
|
K. Okada, J. Shoda, M. Kano, S. Suzuki, N. Ohtake, M. Yamamoto, H. Takahashi, H. Utsunomiya, K. Oda, K. Sato, et al. Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers Am J Physiol Gastrointest Liver Physiol, May 1, 2007; 292(5): G1450 - G1463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Belinsky, P. Guo, K. Lee, F. Zhou, E. Kotova, A. Grinberg, H. Westphal, I. Shchaveleva, A. Klein-Szanto, J. M. Gallo, et al. Multidrug Resistance Protein 4 Protects Bone Marrow, Thymus, Spleen, and Intestine from Nucleotide Analogue-Induced Damage Cancer Res., January 1, 2007; 67(1): 262 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, K.-i. Nezasa, X. Tian, A. S. Bridges, K. Lee, M. G. Belinsky, G. D. Kruh, and K. L. R. Brouwer Evaluation of the Role of Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 in Hepatic Basolateral Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Abcc3-/- and Abcc4-/- Mice J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1485 - 1491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. M. Villanueva, M. L. Ruiz, C. J. Soroka, S.-Y. Cai, M. G. Luquita, A. M. Torres, E. J. Sanchez Pozzi, J. M. Pellegrino, J. L. Boyer, V. A. Catania, et al. HEPATIC AND EXTRAHEPATIC SYNTHESIS AND DISPOSITION OF DINITROPHENYL-S-GLUTATHIONE IN BILE DUCT-LIGATED RATS Drug Metab. Dispos., August 1, 2006; 34(8): 1301 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. H. Vlaming, K. Mohrmann, E. Wagenaar, D. R. de Waart, R. P. J. O. Elferink, J. S. Lagas, O. van Tellingen, L. D. Vainchtein, H. Rosing, J. H. Beijnen, et al. Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies Using Mrp2 (Abcc2) Knockout Mice J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 319 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Ruiz, S. S. M. Villanueva, M. G. Luquita, M. Vore, A. D. Mottino, and V. A. Catania ETHYNYLESTRADIOL INCREASES EXPRESSION AND ACTIVITY OF RAT LIVER MRP3 Drug Metab. Dispos., June 1, 2006; 34(6): 1030 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dallas, D. S. Miller, and R. Bendayan Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol. Rev., June 1, 2006; 58(2): 140 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nishiya, H. Kataoka, K. Mori, M. Goto, T. Sugawara, and K. Furuhama Tienilic Acid Enhances Hyperbilirubinemia in Eisai Hyperbilirubinuria Rats through Hepatic Multidrug Resistance-Associated Protein 3 and Heme Oxygenase-1 Induction Toxicol. Sci., June 1, 2006; 91(2): 651 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Boyer, M. Trauner, A. Mennone, C. J. Soroka, S.-Y. Cai, T. Moustafa, G. Zollner, J. Y. Lee, and N. Ballatori Upregulation of a basolateral FXR-dependent bile acid efflux transporter OST{alpha}-OSTbeta in cholestasis in humans and rodents Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1124 - G1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Y. Chu, J. R. Strauss, M. A. Mariano, J. Li, D. J. Newton, X. Cai, R. W. Wang, J. Yabut, D. P. Hartley, D. C. Evans, et al. Characterization of Mice Lacking the Multidrug Resistance Protein Mrp2 (Abcc2) J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 579 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Frankenberg, A. Rao, F. Chen, J. Haywood, B. L. Shneider, and P. A. Dawson Regulation of the mouse organic solute transporter {alpha}-beta, Ost{alpha}-Ostbeta, by bile acids Am J Physiol Gastrointest Liver Physiol, May 1, 2006; 290(5): G912 - G922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Landrier, J. J. Eloranta, S. R. Vavricka, and G. A. Kullak-Ublick The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-{alpha} and -beta genes Am J Physiol Gastrointest Liver Physiol, March 1, 2006; 290(3): G476 - G485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Aleksunes, G. L. Scheffer, A. B. Jakowski, I. M. Pruimboom-Brees, and J. E. Manautou Coordinated Expression of Multidrug Resistance-Associated Proteins (Mrps) in Mouse Liver during Toxicant-Induced Injury Toxicol. Sci., February 1, 2006; 89(2): 370 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. I. Ghanem, M. L. Ruiz, S. S. M. Villanueva, M. G. Luquita, V. A. Catania, B. Jones, L. A. Bengochea, M. Vore, and A. D. Mottino Shift from Biliary to Urinary Elimination of Acetaminophen-Glucuronide in Acetaminophen-Pretreated Rats J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 987 - 995. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
