The Genetic Polymorphism of Drug Transporters: Functional Analysis Approaches

Ishikawa, Toshihisa; Tsuji, Akira; Inui, Kentaro; Sai, Yoshimichi; Anzai, Naohiko; Wada, Morimasa; Endou, Hitoshi; Sumino, Yasuhiro

doi:10.1517/phgs.5.1.67.25683

Cited by 71 publications

(43 citation statements)

References 157 publications

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“…To clarify the interindividual variation in the pharmacokinetics of drugs, single-nucleotide polymorphisms (SNPs) in the coding region (cSNP) of drug transporters have been investigated (Ishikawa et al, 2004). Erdman et al (2006) examined the allele frequency of several cSNPs in the OAT3 gene and transport characteristics and found that allele frequencies of cSNPs, which resulted in a completed loss of function, were very low (Xu et al, 2005;Erdman et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Human Organic Anion Transporter 3 Gene Is Regulated Constitutively and Inducibly via a cAMP-Response Element

Ogasawara

Takato²,

Asaka³

et al. 2006

J Pharmacol Exp Ther

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Human organic anion transporter (OAT) 3 (SLC22A8) is localized to the basolateral membranes of renal tubular epithelial cells and plays a critical role in the excretion of anionic compounds. We previously reported that interindividual variation in the OAT3 mRNA level corresponded to interindividual differences in the rate of renal excretion of cefazolin. However, there is little information available on the molecular mechanisms regulating the gene expression of OAT3. Therefore, in the present study, we examined the transcriptional regulation of human OAT3. A deletion analysis of the OAT3 promoter suggested that the region spanning Ϫ214 to Ϫ77 base pairs was essential for basal transcriptional activity. This region contained a perfectly conserved cAMP-response element (CRE), and a mutation here led to a reduction in promoter activity. Electrophoretic mobility shift assays showed that CRE-binding protein (CREB)-1 and activating transcription factor (ATF)-1 bound to CRE. The activity of the OAT3 promoter was increased through the phosphorylation of CREB-1 and ATF-1 by treatment with 8-bromo-cAMP. This paper reports the first characterization of the human OAT3 promoter and shows that CREB-1 and ATF-1 function as constitutive and inducible transcriptional regulators of the human OAT3 gene via CRE.

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Section: Discussionmentioning

confidence: 99%

Human Organic Anion Transporter 3 Gene Is Regulated Constitutively and Inducibly via a cAMP-Response Element

Ogasawara

Takato²,

Asaka³

et al. 2006

J Pharmacol Exp Ther

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“…12 In addition to drug-metabolizing enzymes, the clinical significance of genetic variation of drug transporters has been demonstrated. 13 For example, polymorphisms of SLCO1B1, which encodes the organic anion transporting polypeptide 1B1 to mediate the hepatic uptake of pravastatin, contribute to the interindividual variability in the disposition of pravastatin. 14 Recent studies of OCT have demonstrated that polymorphisms of the OCT1 gene in Caucasians and the renal OCT2 gene in Koreans are responsible for the interindividual differences in the therapeutic efficacy and pharmacokinetics of metformin, an anti-diabetic agent.…”

Section: Introductionmentioning

confidence: 99%

Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

et al. 2009

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H + /organic cation antiporters (multidrug and toxin extrusion: MATE1 and MATE2-K) play important roles in the renal tubular secretion of cationic drugs. We have recently identified a regulatory single nucleotide polymorphism (SNP) of the MATE1 gene (À32G4A). There is no other information about SNPs of the MATE gene. In this study, we evaluated the functional significance of genetic polymorphisms in MATE1 and MATE2-K. We sequenced all exons of MATE1 and MATE2-K genes in 89 Japanese subjects and identified coding SNPs (cSNPs) encoding MATE1 (V10L, G64D, A310V, D328A and N474S) and MATE2-K (K64N and G211V). All the variants except for MATE1 V10L showed significant decrease in transport activity. In particular, MATE1 G64D and MATE2-K G211V variants completely lost transport activities. When membrane expression level was evaluated by cell surface biotinylation, those of MATE1 (G64D and D328A) and MATE2-K (K64N and G211V) were significantly decreased compared with that of wild type. These findings suggested that the loss of transport activities of the MATE1 G64D and MATE2-K G211V variants were due to the alteration of protein expression in cell surface membranes. This is the first demonstration of functional impairment of the MATE family induced by cSNPs.

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“…Function analysis of the gene products of some CYPs and transporters, along with their variants, were also conducted. 2 Some of these findings have already been published, and others will be published shortly. Cell lines were also established from the samples and deposited in the Health Science Research Resources Bank.…”

Section: Establishment Of Pharmacoge-nomics Platforms By Industrymentioning

confidence: 95%