This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jonker, J. W.
Right arrow Articles by Schinkel, A. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jonker, J. W.
Right arrow Articles by Schinkel, A. H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2001, p. 5471-5477, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5471-5477.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Reduced Hepatic Uptake and Intestinal Excretion of Organic Cations in Mice with a Targeted Disruption of the Organic Cation Transporter 1 (Oct1 [Slc22a1]) Gene

Johan W. Jonker,1 Els Wagenaar,1 Carla A. A. M. Mol,2 Marije Buitelaar,1 Hermann Koepsell,3 Johan W. Smit,1 and Alfred H. Schinkel1,*

Division of Experimental Therapy1 and Division of Molecular Biology2, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands, and Anatomisches Institut, Bayerische Julius-Maximilians-Universität, 97070 Würzburg, Germany3

Received 7 February 2001/Returned for modification 16 April 2001/Accepted 23 May 2001

The polyspecific organic cation transporter 1 (OCT1 [SLC22A1]) mediates facilitated transport of small (hydrophilic) organic cations. OCT1 is localized at the basolateral membrane of epithelial cells in the liver, kidney, and intestine and could therefore be involved in the elimination of endogenous amines and xenobiotics via these organs. To investigate the pharmacologic and physiologic role of this transport protein, we generated Oct1 knockout (Oct1-/-) mice. Oct1-/- mice appeared to be viable, healthy, and fertile and displayed no obvious phenotypic abnormalities. The role of Oct1 in the pharmacology of substrate drugs was studied by comparing the distribution and excretion of the model substrate tetraethylammonium (TEA) after intravenous administration to wild-type and Oct1-/- mice. In Oct1-/- mice, accumulation of TEA in liver was four to sixfold lower than in wild-type mice, whereas direct intestinal excretion of TEA was reduced about twofold. Excretion of TEA into urine over 1 h was 53% of the dose in wild-type mice, compared to 80% in knockout mice, probably because in Oct1-/- mice less TEA accumulates in the liver and thus more is available for rapid excretion by the kidney. In addition, we found that absence of Oct1 leads to decreased liver accumulation of the anticancer drug metaiodobenzylguanidine and the neurotoxin 1-methyl-4-phenylpyridium. In conclusion, our data show that Oct1 plays an important role in the uptake of organic cations into the liver and in their direct excretion into the lumen of the small intestine.

* Corresponding author. Mailing address: Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31-20-5122046. Fax: 31-20-5122050. E-mail: alfred{at}nki.nl.

Molecular and Cellular Biology, August 2001, p. 5471-5477, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5471-5477.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Zhou, K., Donnelly, L. A., Kimber, C. H., Donnan, P. T., Doney, A. S.F., Leese, G., Hattersley, A. T., McCarthy, M. I., Morris, A. D., Palmer, C. N.A., Pearson, E. R. (2009). Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study. Diabetes 58: 1434-1439 [Abstract] [Full Text]  
  • Tsuda, M., Terada, T., Mizuno, T., Katsura, T., Shimakura, J., Inui, K.-i. (2009). Targeted Disruption of the Multidrug and Toxin Extrusion 1 (Mate1) Gene in Mice Reduces Renal Secretion of Metformin. Mol. Pharmacol. 75: 1280-1286 [Abstract] [Full Text]  
  • Shah, N., Khurana, S., Cheng, K., Raufman, J.-P. (2009). Muscarinic receptors and ligands in cancer. Am. J. Physiol. Cell Physiol. 296: C221-C232 [Abstract] [Full Text]  
  • Zaher, H., zu Schwabedissen, H. E. M., Tirona, R. G., Cox, M. L., Obert, L. A., Agrawal, N., Palandra, J., Stock, J. L., Kim, R. B., Ware, J. A. (2008). Targeted Disruption of Murine Organic Anion-Transporting Polypeptide 1b2 (oatp1b2/Slco1b2) Significantly Alters Disposition of Prototypical Drug Substrates Pravastatin and Rifampin. Mol. Pharmacol. 74: 320-329 [Abstract] [Full Text]  
  • Klaassen, C. D., Lu, H. (2008). Xenobiotic Transporters: Ascribing Function from Gene Knockout and Mutation Studies. Toxicol Sci 101: 186-196 [Abstract] [Full Text]  
  • Maeda, T., Oyabu, M., Yotsumoto, T., Higashi, R., Nagata, K., Yamazoe, Y., Tamai, I. (2007). Effect of Pregnane X Receptor Ligand on Pharmacokinetics of Substrates of Organic Cation Transporter Oct1 in Rats. Drug Metab. Dispos. 35: 1580-1586 [Abstract] [Full Text]  
  • van de Wetering, K., Zelcer, N., Kuil, A., Feddema, W., Hillebrand, M., Vlaming, M. L. H., Schinkel, A. H., Beijnen, J. H., Borst, P. (2007). Multidrug Resistance Proteins 2 and 3 Provide Alternative Routes for Hepatic Excretion of Morphine-Glucuronides. Mol. Pharmacol. 72: 387-394 [Abstract] [Full Text]  
  • Jonker, J. W., Musters, S., Vlaming, M. L. H., Plosch, T., Gooijert, K. E. R., Hillebrand, M. J., Rosing, H., Beijnen, J. H., Verkade, H. J., Schinkel, A. H. (2007). Breast cancer resistance protein (Bcrp1/Abcg2) is expressed in the harderian gland and mediates transport of conjugated protoporphyrin IX. Am. J. Physiol. Cell Physiol. 292: C2204-C2212 [Abstract] [Full Text]  
  • Kang, H.-J., Song, I.-S., Shin, H. J., Kim, W.-Y., Lee, C.-H., Shim, J.-C., Zhou, H.-H., Lee, S. S., Shin, J.-G. (2007). Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population. Drug Metab. Dispos. 35: 667-675 [Abstract] [Full Text]  
  • Michel, V., Yuan, Z., Ramsubir, S., Bakovic, M. (2006). Choline Transport for Phospholipid Synthesis.. Exp. Biol. Med. 231: 490-504 [Abstract] [Full Text]  
  • Fullerton, M. D., Wagner, L., Yuan, Z., Bakovic, M. (2006). Impaired trafficking of choline transporter-like protein-1 at plasma membrane and inhibition of choline transport in THP-1 monocyte-derived macrophages. Am. J. Physiol. Cell Physiol. 290: C1230-C1238 [Abstract] [Full Text]  
  • Tahara, H., Kusuhara, H., Endou, H., Koepsell, H., Imaoka, T., Fuse, E., Sugiyama, Y. (2005). A Species Difference in the Transport Activities of H2 Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters. J. Pharmacol. Exp. Ther. 315: 337-345 [Abstract] [Full Text]  
  • Merino, G., van Herwaarden, A. E., Wagenaar, E., Jonker, J. W., Schinkel, A. H. (2005). Sex-Dependent Expression and Activity of the ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (BCRP/ABCG2) in Liver. Mol. Pharmacol. 67: 1765-1771 [Abstract] [Full Text]  
  • Ishiguro, N., Saito, A., Yokoyama, K., Morikawa, M., Igarashi, T., Tamai, I. (2005). TRANSPORT OF THE DOPAMINE D2 AGONIST PRAMIPEXOLE BY RAT ORGANIC CATION TRANSPORTERS OCT1 AND OCT2 IN KIDNEY. Drug Metab. Dispos. 33: 495-499 [Abstract] [Full Text]  
  • Nie, W., Sweetser, S., Rinella, M., Green, R. M. (2005). Transcriptional regulation of murine Slc22a1 (Oct1) by peroxisome proliferator agonist receptor-{alpha} and -{gamma}. Am. J. Physiol. Gastrointest. Liver Physiol. 288: G207-G212 [Abstract] [Full Text]  
  • Miakotina, O. L., Agassandian, M., Shi, L., Look, D. C., Mallampalli, R. K. (2005). Adenovirus stimulates choline efflux by increasing expression of organic cation transporter-2. Am. J. Physiol. Lung Cell. Mol. Physiol. 288: L93-L102 [Abstract] [Full Text]  
  • Thomas, M. C., Tikellis, C., Kantharidis, P., Burns, W. C., Cooper, M. E., Forbes, J. M. (2004). The Role of Advanced Glycation in Reduced Organic Cation Transport Associated with Experimental Diabetes. J. Pharmacol. Exp. Ther. 311: 456-466 [Abstract] [Full Text]  
  • Wright, S. H., Dantzler, W. H. (2004). Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport. Physiol. Rev. 84: 987-1049 [Abstract] [Full Text]  
  • Jonker, J. W., Schinkel, A. H. (2004). Pharmacological and Physiological Functions of the Polyspecific Organic Cation Transporters: OCT1, 2, and 3 (SLC22A1-3). J. Pharmacol. Exp. Ther. 308: 2-9 [Abstract] [Full Text]  
  • Jonker, J. W., Wagenaar, E., van Eijl, S., Schinkel, A. H. (2003). Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations. Mol. Cell. Biol. 23: 7902-7908 [Abstract] [Full Text]  
  • Mizuno, N., Niwa, T., Yotsumoto, Y., Sugiyama, Y. (2003). Impact of Drug Transporter Studies on Drug Discovery and Development. Pharmacol. Rev. 55: 425-461 [Abstract] [Full Text]  
  • Shu, Y., Leabman, M. K., Feng, B., Mangravite, L. M., Huang, C. C., Stryke, D., Kawamoto, M., Johns, S. J., DeYoung, J., Carlson, E., Ferrin, T. E., Herskowitz, I., Giacomini, K. M., Pharmacogenetics of Membrane Transporters Investig, (2003). Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc. Natl. Acad. Sci. USA 100: 5902-5907 [Abstract] [Full Text]  
  • Wang, D.-S., Kusuhara, H., Kato, Y., Jonker, J. W., Schinkel, A. H., Sugiyama, Y. (2003). Involvement of Organic Cation Transporter 1 in the Lactic Acidosis Caused by Metformin. Mol. Pharmacol. 63: 844-848 [Abstract] [Full Text]  
  • Burckhardt, B. C., Brai, S., Wallis, S., Krick, W., Wolff, N. A., Burckhardt, G. (2003). Transport of cimetidine by flounder and human renal organic anion transporter 1. Am. J. Physiol. Renal Physiol. 284: F503-F509 [Abstract] [Full Text]  
  • Siegel, J. A., Stabin, M. G., Sparks, R. B., Huberty, J., Matthay, K. K., Hawkins, R., Hasegawa, B. (2003). Total-Body and Red Marrow Dose Estimates. JNM 44: 320-323 [Full Text]  
  • Jonker, J. W., Buitelaar, M., Wagenaar, E., van der Valk, M. A., Scheffer, G. L., Scheper, R. J., Plosch, T., Kuipers, F., Elferink, R. P. J. O., Rosing, H., Beijnen, J. H., Schinkel, A. H. (2002). The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc. Natl. Acad. Sci. USA 99: 15649-15654 [Abstract] [Full Text]  
  • Wang, D.-S., Jonker, J. W., Kato, Y., Kusuhara, H., Schinkel, A. H., Sugiyama, Y. (2002). Involvement of Organic Cation Transporter 1 in Hepatic and Intestinal Distribution of Metformin. J. Pharmacol. Exp. Ther. 302: 510-515 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»