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