Elsevier

Biochemical Pharmacology

Volume 73, Issue 3, 1 February 2007, Pages 440-449
Biochemical Pharmacology

Gene expression and regulation of drug transporters in the intestine and kidney

https://doi.org/10.1016/j.bcp.2006.10.010Get rights and content

Abstract

Intestinal absorption and renal secretion of ionic drugs are controlled by a number of drug transporters expressed at the brush-border and basolateral membranes of epithelial cells. Over the last several years, considerable progress has been made regarding the molecular identification and functional characterization of drug transporters. Under some physiological and pathophysiological conditions, the expression and transport activity of drug transporters are changed, affecting the pharmacokinetics of substrate drugs. The regulation of transport activity in response to endogenous and exogenous signals can occur at various levels such as transcription, mRNA stability, translation, and posttranslational modification. Transcriptional regulation is of particular interest, because changes in transport activity are dynamically regulated by increases or decreases in levels of mRNA expression. The tissue-specific expression of drug transporters is also under transcriptional control, and recent studies using clinical samples from human tissues have revealed the expression profiles of drug transporters in the human body. The purpose of this research updates is to review the recent progress in the study of the gene expression and regulation of intestinal and renal drug transporters.

Introduction

Mucosal surfaces of tissues such as the intestine and kidney are lined by a single layer of epithelial cells. Epithelial cells function as a barrier to select essential (such as nutrients) and waste (such as toxic xenobiotics) compounds, being equipped with uptake and efflux transport systems. During the last decade, many kinds of nutrient and drug transporters in the intestine and kidney have been identified as uptake and efflux transport systems. Currently, various transporters have been classified as ATP-binding cassette (ABC) transporters and solute carriers (SLCs) based on sequence similarity by the Human Gene Nomenclature Committee.

In general, nutrient transporters in the intestine are tightly regulated by nutrient load [1]. Observed patterns of response for essential nutrients and/or nutrients that are toxic in excess, such as zinc and iron, are generally consistent with the maintenance of the body's nutrient status under conditions of variable intake. For example, expression of the divalent metal ion transporter (DMT1/SLC11A2), involved in iron absorption, is increased in the intestine by an iron-deficient diet [2]. Drug transporters are also regulated by many biochemical signalling pathways, and such regulation may influence the pharmacokinetics of substrate drugs. The regulation of transport activity in response to endogenous and exogenous signals may occur at various levels such as transcription, mRNA stability, translation, and posttranslational modification (Fig. 1). This diversity of regulatory mechanisms may be advantageous to correspond to various biological signals. In general, transcriptional regulation and posttranslational modification are believed to be responsible for long-term and short-term regulation, respectively. We are interested in the transcriptional regulation of drug transporters, because changes in transport activity are dynamically regulated by increases or decreases in levels of mRNA expression. The tissue-specific expression of drug transporters is also under transcriptional control, although there is little information about the mechanisms behind intestinal and renal-specific expression.

This research updates will focus on our current understanding of the expression and gene regulation of drug transporters in the intestine and kidney, concentrating on the control mechanisms governing the expression of each transporter. For SLC drug transporters, H+/peptide transporters (PEPT) and organic ion transporters (OCT/OCTN/OAT) were selected as representative of transporters expressed in the intestine and kidney. The transporters mainly referred to here are listed in Table 1. On the other hand, only the expression profiles of ABC transporters are covered in this article. We do not refer to the gene regulation of ABC transporters, because several excellent reviews about gene regulation of ABC transporters have been already published [3], [4], [5], [6].

Section snippets

General function and pharmacokinetic roles

H+/peptide cotransporter 1 (PEPT1, SLC15A) is localized at the brush-border membranes of intestinal epithelial cells and plays an important role for protein absorption to mediate the cellular uptake of di- and tripeptides digested from ingested food [7]. Because of its broad substrate specificity, PEPT1 recognizes various peptide-like drugs such as oral β-lactam antibiotics, which are structurally resemble to small peptides [8]. Intestinal PEPT1 can be utilized as a target for improving the

Expression profile of human intestinal and renal drug transporters

The development of quantitative real-time PCR techniques has meant that expression levels of drug transporters can be quantitatively determined using a very small amount of tissue sample. Recently, based on these techniques, expression profiles of various genes including those for human drug transporters have been determined using surplus tissue specimens collected during surgery or biopsy.

Conclusions and future perspectives

In these research updates, we addressed recent advances in the study of the gene regulation and expression of drug transporters in the intestine and kidney. Among drug transporters, MDR1 has been well studied in terms of its gene regulation, and many transcription factors for MDR1 gene have been identified [3], [4]. On the other hand, the history of gene regulation for intestinal and renal drug transporters is very short. For example, the transcription factors Sp1, Cdx2 and PPARα were just

References (88)

  • M. Inoue et al.

    Regulation of human peptide transporter 1 (PEPT1) in gastric cancer cells by anticancer drugs

    Cancer Lett

    (2005)
  • Y.J. Fei et al.

    cDNA structure, genomic organization, and promoter analysis of the mouse intestinal peptide transporter PEPT1

    Biochim Biophys Acta

    (2000)
  • J. Shimakura et al.

    The transcription factor Cdx2 regulates the intestine-specific expression of human peptide transporter 1 through functional interaction with Sp1

    Biochem Pharmacol

    (2006)
  • H. Shen et al.

    Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in choroid plexus

    J Biol Chem

    (2003)
  • H. Lu et al.

    Tissue distribution and thyroid hormone regulation of Pept1 and Pept2 mRNA in rodents

    Peptides

    (2006)
  • N. Nakamura et al.

    Decreased expression of glucose and peptide transporters in rat remnant kidney

    Drug Metab Pharmacokinet

    (2004)
  • I. Rubio-Aliaga et al.

    Cloning and characterization of the gene encoding the mouse peptide transporter PEPT2

    Biochem Biophys Res Commun

    (2000)
  • K. Inui et al.

    Cellular and molecular aspects of drug transport in the kidney

    Kidney Int

    (2000)
  • R.R. Ramsay et al.

    Molecular enzymology of carnitine transfer and transport

    Biochim Biophys Acta

    (2001)
  • Y. Urakami et al.

    Hormonal regulation of organic cation transporter OCT2 expression in rat kidney

    FEBS Lett

    (2000)
  • L. Ji et al.

    Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy

    Kidney Int

    (2002)
  • Y. Urakami et al.

    Gender differences in expression of organic cation transporter OCT2 in rat kidney

    FEBS Lett

    (1999)
  • S.A. Terlouw et al.

    Modulatory effects of hormones, drugs, and toxic events on renal organic anion transport

    Biochem Pharmacol

    (2003)
  • Y. Habu et al.

    Decreased activity of basolateral organic ion transports in hyperuricemic rat kidney: roles of organic ion transporters, rOAT1, rOAT3 and rOCT2

    Biochem Pharmacol

    (2003)
  • H. Ueo et al.

    Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1

    Biochem Pharmacol

    (2005)
  • T. Terada et al.

    Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract

    Biochem Pharmacol

    (2005)
  • H. Gutmann et al.

    Distribution of breast cancer resistance protein (BCRP/ABCG2) mRNA expression along the human GI tract

    Biochem Pharmacol

    (2005)
  • R.A. Cragg et al.

    Homeostatic regulation of zinc transporters in the human small intestine by dietary zinc supplementation

    Gut

    (2005)
  • H. Gunshin et al.

    Cloning and characterization of a mammalian proton-coupled metal-ion transporter

    Nature

    (1997)
  • K.W. Scotto

    Transcriptional regulation of ABC drug transporters

    Oncogene

    (2003)
  • P.M. Gerk et al.

    Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition

    J Pharmacol Exp Ther

    (2002)
  • A. Haimeur et al.

    The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation

    Curr Drug Metab

    (2004)
  • H. Daniel

    Molecular and integrative physiology of intestinal peptide transport

    Annu Rev Physiol

    (2004)
  • T. Terada et al.

    Peptide transporters: structure, function, regulation and application for drug delivery

    Curr Drug Metab

    (2004)
  • H. Han et al.

    5′-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter

    Pharm Res

    (1998)
  • M. Irie et al.

    Computational modelling of H+-coupled peptide transport via human PEPT1

    J Physiol

    (2005)
  • M. Sala-Rabanal et al.

    Molecular interactions between dipeptides, drugs and the human intestinal H+-oligopeptide cotransporter hPEPT1

    J Physiol

    (2006)
  • S.A. Adibi

    Regulation of expression of the intestinal oligopeptide transporter (Pept-1) in health and disease

    Am J Physiol Gastrointest Liver Physiol

    (2003)
  • D. Walker et al.

    Substrate upregulation of the human small intestinal peptide transporter, hPepT1

    J Physiol

    (1998)
  • M. Thamotharan et al.

    Hormonal regulation of oligopeptide transporter pept-1 in a human intestinal cell line

    Am J Physiol

    (1999)
  • M. Buyse et al.

    PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine

    J Clin Invest

    (2001)
  • K. Ashida et al.

    Thyroid hormone regulates the activity and expression of the peptide transporter PEPT1 in Caco-2 cells

    Am J Physiol Gastrointest Liver Physiol

    (2002)
  • S.R. Vavricka et al.

    Tumor necrosis factor-alpha and interferon-gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine

    Pflügers Arch

    (2006)
  • H. Shen et al.

    Developmental expression of PEPT1 and PEPT2 in rat small intestine, colon, and kidney

    Pediatr Res

    (2001)
  • Cited by (68)

    • The SUMO-Specific Protease Senp2 Regulates SUMOylation, Expression and Function of Human Organic Anion Transporter 3

      2019, Biochimica et Biophysica Acta - Biomembranes
      Citation Excerpt :

      These results further confirmed that there was a direct interaction between Oat3 and Senp2 not only in vitro but also in vivo. Active drug transport mediated by OATs is a major determining factor of the outcomes of therapeutical reagents and toxic chemicals [1–6]. Hence, mechanistic understanding of OAT regulation is clinically and pharmacologically significant.

    View all citing articles on Scopus

    This work was supported by the 21st Century COE Program “Knowledge Information Infrastructure for Genome Science”, a Grant-in-Aid from the Japan Health Sciences Foundation, and a Grant-in-Aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan.

    View full text