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

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)42-50
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume335
Issue number1
DOIs
Publication statusPublished - 01-01-2010

Fingerprint

Organic Cation Transporter 1
Genetic Polymorphisms
Metformin
Population
Green Fluorescent Proteins
Type 2 Diabetes Mellitus
Hypoglycemic Agents
Gene Frequency
Endoplasmic Reticulum
Cell Membrane
Genome
Amino Acids

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Chen, Ligong ; Takizawa, Miho ; Chen, Eugene ; Schlessinger, Avner ; Segenthelar, Julie ; Choi, Ji Ha ; Sali, Andej ; Kubo, Michiaki ; Nakamura, Shinko ; Iwamoto, Yasuhiko ; Iwasaki, Naoko ; Giacomini, Kathleen M. / Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 335, No. 1. pp. 42-50.
@article{afb23bf139794162a52cbfe22db71a69,
title = "Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function",
abstract = "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.",
author = "Ligong Chen and Miho Takizawa and Eugene Chen and Avner Schlessinger and Julie Segenthelar and Choi, {Ji Ha} and Andej Sali and Michiaki Kubo and Shinko Nakamura and Yasuhiko Iwamoto and Naoko Iwasaki and Giacomini, {Kathleen M.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1124/jpet.110.170159",
language = "English",
volume = "335",
pages = "42--50",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

Chen, L, Takizawa, M, Chen, E, Schlessinger, A, Segenthelar, J, Choi, JH, Sali, A, Kubo, M, Nakamura, S, Iwamoto, Y, Iwasaki, N & Giacomini, KM 2010, 'Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function', Journal of Pharmacology and Experimental Therapeutics, vol. 335, no. 1, pp. 42-50. https://doi.org/10.1124/jpet.110.170159

Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. / Chen, Ligong; Takizawa, Miho; Chen, Eugene; Schlessinger, Avner; Segenthelar, Julie; Choi, Ji Ha; Sali, Andej; Kubo, Michiaki; Nakamura, Shinko; Iwamoto, Yasuhiko; Iwasaki, Naoko; Giacomini, Kathleen M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 335, No. 1, 01.01.2010, p. 42-50.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function

AU - Chen, Ligong

AU - Takizawa, Miho

AU - Chen, Eugene

AU - Schlessinger, Avner

AU - Segenthelar, Julie

AU - Choi, Ji Ha

AU - Sali, Andej

AU - Kubo, Michiaki

AU - Nakamura, Shinko

AU - Iwamoto, Yasuhiko

AU - Iwasaki, Naoko

AU - Giacomini, Kathleen M.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77957238214&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957238214&partnerID=8YFLogxK

U2 - 10.1124/jpet.110.170159

DO - 10.1124/jpet.110.170159

M3 - Article

VL - 335

SP - 42

EP - 50

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -