Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population

Abstract

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 those genetic polymorphisms of hOCTs were compared among different ethnic populations. From direct DNA sequencing, 7 of 13 coding variants were nonsynonymous single-nucleotide polymorphisms (SNPs), including four variants from hOCT1 (F160L, P283L, P341L, and M408V) and three from hOCT2 (T199I, T201M, and A270S), whereas 6 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 overexpress the hOCT2-T199I, -T201M, and -A270S variants showed significantly decreased uptake of showed a 2-to 5-fold increase in K m values and a 10-to 20-fold decrease in V max 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 from those of Chinese and Vietnamese populations. These findings suggest that genetic variants of hOCTs are not linked among three genes in a Korean population, and several of the hOCT genetic variants cause decreased transport activity in vitro compared with the wild type, although the clinical relevance of these variants remains to be evaluated.The human organic cation transporters hOCT1, hOCT2, and hOCT3 mediate electrogenic transport of small organic cations with different molecular structures, independent of sodium gradient (Koepsell, 1999). These organic cation substrates include clinically important therapeutics (e.g., metformin, procainamide, and cimetidine), endogenous compounds (e.g., dopamine and norepinephrine), as well as toxic substances [e.g., tetraethylammonium bromide (TEA), HPP ϩ , and methyl-4-phenylpyridinium acetate (MPP ϩ )] (Gorboulev et al., 1997;Zhang et al., 1997;Kang et al., 2006). Although these transporters show extensive overlaps in their substrate specificities, they exhibit distinct differences in tissue distribution; hOCT1 is primarily found in the sinusoidal membrane of hepatocytes and, to a lesser extent, in intestinal epithelial cells, whereas hOCT2 is mainly expressed in the basolateral membrane of kidney proximal tubules, and hOCT3 shows a widespread tissue distribution that includes the brain, heart, and liver. Based on their properties and tissue distributions, hOCT1, hOCT2, and hOCT3 are thought to play important roles in the excretion and distribution of organic cations in the liver, kidney, and brain (Jonker and Schinkel, 2004).Knockout mouse models have been generated for the Oct1, Oct2, and Oct3 genes to elucidate the in vivo function of the OCT transporters. Oct1-, Oct2-, and Oct3-deficient mice are viable and display no obvious phenotypic abnormalities (Jonker et al., 2001Zwart et al., 2001...

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

“…5A) was found, which was in line with data from a Korean population. 53 Remarkably, the haploblock structure of our 150 liver bank samples (Fig. 5A) is comparable to the HapMap data of northern/western Europeans (Supporting Fig.…”

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

“…This analysis showed that there were three genotypes (GG, GT, and TT) at position 808 in the SLC22A2 gene in Chinese Hans with T2DM. The genotype in the two groups and the total group were in accordance with Hardy-Weinberg equilibrium, and the T allele frequency was 12.9%, which was similar to the data in healthy populations from Hong Kong (13.3%), Japan (16.8%), and Korea (11%) [13,20,21] . This research further investigated the relationship between the SLC22A2 808G>T polymorphism and plasma lactate levels in these T2DM patients treated with or without metformin.…”

Organic Cation Transporter Variation and Response to Smoking Cessation Therapies

“…77 Consistent with most of the clinical data except the study of Chen et al 73 , the in vitro functional literature suggests that the effect of the rs316019 minor allele is associated with significant reductions in the transport of model OCT2 substrates. 78,79 Thus ~19%-28% of European, East Asian, and Yoruban ancestry populations may be carriers of a reduced function OCT2 protein. Further in vivo and in vitro research on OCT2 variation and effects on drug disposition is needed.…”