Multidrug and toxin extrusion 1 (MATE1, SLC47A1), an organic cation transporter, plays an important role in the renal and biliary elimination of various clinical drugs, including the anti-diabetic drug metformin. The goal of this study was to identify and characterize novel genetic variants of MATE1. Five variants in the promoter region and two nonsynonymous variants, p.D64G and p.L125F, were identified in 48 DNA samples from healthy Koreans. MATE1 promoter haplotype 3 containing g.-1975C>A showed a significant increase in reporter activity. Three transcription factors, Nkx-2.5, SREBP-1, and USF-1 were predicted to bind to the promoter in the region of g.-1975C>A. Results from electrophoretic mobility shift assays showed that the g.-1975A allele exhibits greater binding affinity to all of these transcription factors than the g.-1975C allele. In particular, we found that Nkx-2.5 and USF-1 induce MATE1 transcription. Our study suggests that the common promoter haplotype of MATE1 changes MATE1 transcriptional activity regulated by Nkx-2.5, SREBP-1, and USF-1.
|Number of pages||7|
|Journal||Biochemical and Biophysical Research Communications|
|State||Published - 3 May 2013|
Bibliographical noteFunding Information:
This study was supported by grant of the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare , Republic of Korea [ A111218-PG03 ], the National Research Foundation (NRF) grant funded by the Korea government (MEST) [ 2012-0009844 ], and the Ewha Womans University Research Grant of 2009 . We thank Dr. I. Jang and Dr. J. Cho for their help in obtaining genomic DNA samples from the DNA bank of the Korea Pharmacogenomics Research Network at Seoul National University. We also thank Dr. J. Chung for his help in retrospective analysis of DNA samples from metformin pharmacokinetic study.