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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.


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