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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/F1564    most recent 00322.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Kajiwara, M. Articles by Inui, K.-i. Search for Related Content PubMed PubMed Citation Articles by Kajiwara, M. Articles by Inui, K.-i.

Critical roles of Sp1 in gene expression of human and rat H⁺/organic cation antiporter MATE1

¹Department of Pharmacy, ²Department of Urology, and ³Division of Artificial Kidneys, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto; and ⁴Department of Clinical Biology and Medicine, University of Tokushima, Tokushima, Japan

Submitted 13 July 2007 ; accepted in final form 10 September 2007

A H⁺/organic cation antiporter (multidrug and toxin extrusion 1: MATE1/SLC47A1) plays important roles in the tubular secretion of various clinically important cationic drugs such as cimetidine. We have recently found that the regulation of this transporter greatly affects the pharmacokinetic properties of cationic drugs in vivo. No information is available about the regulatory mechanisms for the MATE1 gene. In the present study, therefore, we examined the gene regulation of human (h) and rat (r) MATE1, focusing on basal expression. A deletion analysis suggested that the regions spanning –65/–25 and –146/–38 were essential for the basal transcriptional activity of the hMATE1 and rMATE1 promoter, respectively, and that both regions contained putative Sp1-binding sites. Functional involvement of Sp1 was confirmed by Sp1 overexpression, a mutational analysis of Sp1-binding sites, mithramycin A treatment, and an electrophoretic mobility shift assay. Furthermore, we found a single nucleotide polymorphism (SNP) in the promoter region of hMATE1 (G–32A), which belongs to a Sp1-binding site. The allelic frequency of this rSNP was 3.7%, and Sp1-binding and promoter activity were significantly decreased. This is the first study to clarify the transcriptional mechanisms of the MATE1 gene and to identify a SNP affecting the promoter activity of hMATE1.

tubular secretion; basal transcriptional activity; single nucleotide polymorphism; multidrug and toxin extrusion 1