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Novel organic cation transporter 2 (OCTN2) is a multispecific, bidirectional, pH-dependent organic cation transporter. It can function as a carnitine co-transporter with higher affinity for carnitine than OCTN1 but also functions as a uniporter for other cations. Drugs such as verapamil, pyrilamine and beta-lactam antibiotics have been characterized as substrates of OCTN2 and/or inhibitors of carnitine transport. This study identified variants of the SLC22A5 gene in two distinct ethnic groups of the Singaporean population (n=192) by DNA sequencing. Twenty-eight genetic variants of SLC22A5, including 13 that were novel, were found: 14 were located in the coding exons, 10 in the introns, 1 in the promoter region, 2 in the 5'-untranslated region and 1 in the 3'-untranslated region. Among the novel nonsynonymous variants, Asp122Tyr was predicted to be functionally significant. Functional nonsynonymous variants detected include Ser467Cys and Arg254X; the latter resulted in a premature stop codon and is predicted to result in a truncated protein that is less than half the molecular mass of wild-type OCTN2. These data constitute fundamental information of value for future pharmacogenetic studies in Asian populations on drugs that are substrates of OCTN2.

The novel organic cation transporter 1 (OCTN1) is a multispecific, bidirectional and pH-dependent organic cation transporter with low carnitine transport activity. It is a transporter of the physiological substance ergothioneine and mediates the transport of a variety of organic cations such as tetraethylammonium, pyrilamine and quinidine. This study identifies genetic variations of the SLC22A4 gene in two distinct ethnic groups of the Singaporean population (n=192) by DNA sequencing. Twenty four genetic variants of SLC22A4, including 14 found to be novel. 16 in the coding exons (10 nonsynonymous and 6 synonymous variations) and 8 in the introns. Among the novel nonsynonymous variations, Arg63His, Arg83Pro, Met344Lys and Ile500Asn were predicted to be functionally significant. These data should provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of OCTN1 in Asians.

MRP2 is a drug transporter that is responsible for the gastrointestinal absorption and biliary excretion of a wide variety of endogenous and xenobiotic compounds, including many clinically used drugs. This study aims to identify genetic variations of ABCC2 gene in three distinct ethnic groups of the Singaporean population (n = 288). The coding region of the gene encoding the transporter protein was screened for genetic variations in the study population by denaturing high-performance liquid chromatography and DNA sequencing. Twenty-two genetic variations of ABCC2, including 8 novel ones, were found: 1 in the 5' untranslated region, 10 in the coding exons (8 nonsynonymous and 2 synonymous variations), and 11 in the introns. Three novel nonsynonymous variations: 2686G > A (Glu896Lys), 4240C > T (His1414Tyr) and 4568A > C (Gln1523Pro) were detected in single heterozygous Malay, Chinese, and Indian subjects, respectively. Among the novel nonsynonymous variations, 4240C > T and 4568A > C were predicted to be functionally significant. These data would provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of MRP2 in Asians.

OATP1B1 is a liver-specific transporter that mediates the uptake of various endogenous and exogenous compounds including many clinically used drugs from blood into hepatocytes. This study aims to identify genetic variations of SLCO1B1 gene in three distinct ethnic groups of the Singaporean population (n=288). The coding region of the gene encoding the transporter protein was screened for genetic variations in the study population by denaturing high-performance liquid chromatography and DNA sequencing. Twenty-five genetic variations of SLCO1B1, including 10 novel ones, were found: 13 in the coding exons (9 nonsynonymous and 4 synonymous variations), 6 in the introns, and 6 in the 3' untranslated region. Four novel nonsynonymous variations: 633AG (Ile211Met), 875CT (Ala292Val), 1837TC (Cys613Arg), and 1877TA (Leu626Stop) were detected as heterozygotes. Among the novel nonsynonymous variations, 633AG, 1837TC, and 1877TA were predicted to be functionally significant. These data would provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of OATP1B1 in Asians.

The human concentrative nucleoside transporter 2 (hCNT2) plays a major role in the intestinal absorption of naturally occurring nucleosides as well as some nucleoside analog drugs. To determine if single nucleotide polymorphisms (SNPs) in the promoter region of hCNT2 affect gene expression, we examined approximately 1 kb upstream the hCNT2 transcription start site. Ninety Chinese samples were screened and seven SNPs were identified: -115T>G, -146T>A, -264A>G, -564G>A, -861A>C, -880T>C and -906C>T. Based on these seven variants and their relative positions, eight haplotypes were identified using PHASE v2.1.1. Three naturally occurring haplotypes were cloned into the pGL3-Basic vector and transfected into HEK293 cells. Dual luciferase assay revealed that haplotype 4 (GTAGACC) and 7 (GAGAACT) exhibited significantly lower expression levels compared to the published haplotype 1 (TTAGATC). Results from our in-vitro study showed that the hCNT2 promoter region haplotype may modulate gene expression and cause different drug responses.