Pregnane X Receptor agonist Increases the Expression Levels of the Plasma Membrane Monoamine Transporter

Sung Kweon Cho; Haejin Oh; Se Hyang Hong; Min Soo Park; Jae Yong Chung

doi:10.12793/tcp.2014.22.1.19

Journal List > Transl Clin Pharmacol > v.22(1) > 1082587

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Cho, Oh, Hong, Park, and Chung: Pregnane X Receptor agonist Increases the Expression Levels of the Plasma Membrane Monoamine Transporter

Original Article

Translational and Clinical Pharmacology 2014;22(1):19-21.

Published online: 30 June 2014

DOI: https://doi.org/10.12793/tcp.2014.22.1.19

Pregnane X Receptor agonist Increases the Expression Levels of the Plasma Membrane Monoamine Transporter

Sung Kweon Cho¹, Haejin Oh², Se Hyang Hong², Min Soo Park^3,, Jae Yong Chung^4,^∗,

¹Department of Pharmacology, Yonsei University College of Medicine, Seoul 120–752, Korea

²Clinical Trial Center, Yonsei University, Seoul 120–752, Korea

³Department of Pediatrics, Yonsei University College of Medicine, Seoul 120–752, Korea

⁴Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam 463–707, Korea

^∗Correspondence: J. Y. Chung; Tel: +82-31-787-3955, Fax: +82-31-787-4045, E-mail: jychung@snubh.org;

M. S. Park; Tel: +82-2-2228-0400, Fax: +82-2-2227-7890, E-mail: minspark@yuhs.ac

S.K.Cho and H.Oh contributed equally to this study.

Received 17 April 2014 Revised 14 May 2014 Accepted 14 May 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We evaluated the effect of the pregnane X receptor agonist, pregnenolone 16 alpha-carbonitrile (PCN) on the expression levels of plasma monoamine transporter (PMAT) in the intestine. Male C57/BL6 mice were divided into two 2 groups: mice in the PCN group (n=3) were administered PCN once a day for 4 days, while those in the control group (n=3) received the same volume of vehicle once a day for 4 days. After the mice were killed 24 h after administration of the last dose of PCN or vehicle, and the expression levels of PMAT in the intestine tissues were isolated and measured the expression level of PMAT using immunohistochemical and western blotting analyses. The expression level of PMAT expression levels in the small intestine increased after PCN treatment. These results suggest that the induction of PMAT may play a clinically significant role by increasing intestinal absorption of PMAT substrates such as metformin.

Keywords: PXR, PMAT, PCN, Expression

References

1. Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007; 74:359–371.

2. Sugawara-Yokoo M, Urakami Y, Koyama H, Fujikura K, Masuda S, Saito H, et al. Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules. Histochem Cell Biol. 2000; 114:175–180.

3. Engel K, Zhou M, Wang J. Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem. 2004; 279:50042–5049.

4. Ho HT, Pan Y, Cui Z, Duan H, Swaan PW, Wang J. Molecular analysis and structure-activity relationship modeling of the substrate/inhibitor interaction site of plasma membrane monoamine transporter. J Pharmacol Exp Ther. 2011; 339:376–385.

5. Engel K, Wang J. Interaction of organic cations with a newly identified plasma membrane monoamine transporter. Mol Pharmacol. 2005; 68:1397–1407.

6. Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos. 2007; 35:1956–1962.

7. Xia L, Zhou M, Kalhorn TF, Ho HT, Wang J. Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleo-side nephrotoxicity. Am J Physiol Renal Physiol. 2009; 296:F1307–F1313.

8. Cho SK, Yoon JS, Lee MG, Lee DH, Lim LA, Park K, et al. Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. Clin Pharmacol Ther. 2011; 89:416–421.

9. Lickteig AJ, Cheng X, Augustine LM, Klaassen CD, Cherrington NJ. Tissue distribution, ontogeny and induction of the transporters Multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci. 2008; 83:59–64.

10. Maeda T, Oyabu M, Yotsumoto T, Higashi R, Nagata K, Yamazoe Y, et al. Effect of pregnane X receptor ligand on pharmacokinetics of substrates of organic cation transporter Oct1 in rats. Drug Metab Dispos. 2007; 35:1580–1586.

11. Kim W, Seong J, An JH, Oh HJ. Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma. J Radiat Res. 2007; 48:187–195.

12. Seong J, Oh HJ, Kim J, An JH, Kim W. Identification of proteins that regulate radiation-induced apoptosis in murine tumors with wild type p 53. J Radiat Res. 2007; 48:435–441.

13. Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009; 50:1227–1240.

14. Nie W, Sweetser S, Rinella M, Green RM. Transcriptional regulation of murine Slc22a1 (Oct1) by peroxisome proliferator agonist receptor-alpha and -gamma. Am J Physiol Gastrointest Liver Physiol. 2005; 288:G207–G212.

15. Xu S, Sun AQ, Suchy FJ. A novel RARα/CAR-mediated mechanism for regulation of human organic solute transporter-β gene expression. Am J Physiol Gastrointest Liver Physiol. 2014; 306:G154–162.

Figure 1.

Effect of pregnenolone 16 alpha-carbonitrile (PCN) on PMAT expression in C57/BL6 mice. Representative immunohistochemical images for PMAT staining in the small intestine in the control (left) and PCN (right) animals.

Figure 2.

The effect of PCN on PMAT expression in the liver and small intestine as assessed using western blotting analyses (samples were pooled).

TOOLS

Similar articles