Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function

Ligong Chen, Miho Takizawa, Eugene Chen, Avner Schlessinger, Julie Segenthelar, Ji Ha Choi, Andej Sali, Michiaki Kubo, Shinko Nakamura, Yasuhiko Iwamoto, Naoko Iwasaki, Kathleen M. Giacomini

研究成果: Article査読

58 被引用数 (Scopus)

抄録

Organic cation transporter 1 (OCT1; SLC22A1) seems to play a role in the efficacy and disposition of the widely used antidiabetic drug metformin. Genetic variants in OCT1 have been identified largely in European populations. Metformin is increasingly being used in Asian populations where the incidence of type 2 diabetes (T2D) is on the rise. The goal of this study is to identify genetic variants of OCT1 in Chinese and Japanese populations, which may potentially modulate response to metformin. We used recent data from the 1000 Genomes Project (Chinese and Japanese) and direct sequencing of selected amplicons of OCT1 in 66 DNA samples from Japanese patients with T2D. A total of six nonsynonymous variants were identified. Three of them (Q97K, P117L, and R206C) had not been functionally characterized previously and had allele frequencies of 0.017, 0.023 and 0.008, respectively. The uptake of metformin in cells expressing Q97K, P117L, and R206C was significantly reduced relative to the OCT1 reference (62 ± 4.3, 55 ± 6.8, and 22 ± 1.5% for Q97K, P117L, and R206C, respectively). Kinetic studies indicated that P117L and R206C exhibited a reduced Vmax, whereas Q97K showed an increased Km. The green fluorescent protein (GFP)-tagged Q97K and P117L variants localized to the plasma membrane, whereas the GFP-tagged R206C was retained mainly in the endoplasmic reticulum. Replacement of the highly conserved R206 with different amino acids modulated the subcellular localization and function of the transporter. This study suggests that non-synonymous variants of OCT1 in Chinese and Japanese populations may affect the differential response to metformin.

本文言語English
ページ(範囲)42-50
ページ数9
ジャーナルJournal of Pharmacology and Experimental Therapeutics
335
1
DOI
出版ステータスPublished - 10-2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

フィンガープリント 「Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル