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Drug Metabolism and Disposition Fast Forward
First published on January 12, 2007; DOI: 10.1124/dmd.106.013581

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Received for publication October 30, 2006.
Revised January 10, 2007.
Accepted for publication January 11, 2007.

IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF GENETIC VARIANTS OF HUMAN ORGANIC CATION TRANSPORTERS (hOCTs) IN A KOREAN POPULATION

Ho-Jin kang 1, Im-Sook Song 1, Ho-Jung Shin 1, Woo-Young Kim 1, Choong-Hee Lee 1, Joo-Cheol Shim 1, Hong-Hao Zhou 2, Sang Seop Lee 1, Jae-Gook Shin 1*

1 Department of Pharmacology and Pharmacogenomics Research Center 2 Institute of Clinical Pharmacology, Xiang-Ya School of Medicine

* Address correspondence to: E-mail: phshinjg{at}inje.ac.kr

Abstract

Genetic variants of three human organic cation transporter genes (hOCTs) were extensively explored in a Korean population, the functional changes of hOCT2 variants were evaluated in vitro, and also compared those genetic polymorphisms of hOCTs among different ethnic populations. From direct DNA sequencing, Seven of 13 coding variants were non-synonymous SNPs including four variants from hOCT1 (F160L, P283L, P341L, and M408V) and three from hOCT2 (T199I, T201M, and A270S), while six were synonymous SNPs. The linkage disequilibrium analysis presented for three independent LD blocks for each hOCT gene showed no significant linkage among all three hOCT genes. The transporter activities of MDCK cells that overexpressing the hOCT2-T199I, -T201M, and -A270S variants showed significantly decreased uptake of [3H]MPP+ or [14C]TEA compared to those cells that overexpressing wild-type hOCT2, and the estimated kinetic parameters of these variants for [3H]MPP+ uptake in oocytes showed a 2-5-fold increase in Km values and a 10-20-fold decrease in Vmax values. The allele frequencies of the five functional variants hOCT1-P283L, -P341L, and hOCT2-T199I, -T201M, and -A270S were 1.3, 17, 0.7, 0.7, and 11%, respectively, in a Korean population; the frequency distributions of these variants were not significantly different to those of Chinese and Vietnamese populations. These findings suggest that genetic variants of hOCTs are not linked among 3 genes in a Korean population, and several of the hOCT genetic variants cause decreased transport activity in vitro compared to the wild type although the clinical relevance of these variants remains to be evaluated.


Key words: DNA mutagenesis, drug absorption, drug disposition, genetic polymorphism, kinetics, organic cation transport, transporters


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O. Zolk, T. F. Solbach, J. Konig, and M. F. Fromm
Functional Characterization of the Human Organic Cation Transporter 2 Variant p.270Ala>Ser
Drug Metab. Dispos., June 1, 2009; 37(6): 1312 - 1318.
[Abstract] [Full Text] [PDF]


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