Seven Novel Single Nucleotide Polymorphisms in the Human SLC22A1 Gene Encoding Organic Cation Transporter 1 (OCT1)

Itoda, Masaya; Saito, Yoshiro; Maekawa, Keiko; Hichiya, Hiroyuki; Komamura, Kazuo; Kamakura, Shiro; Kitakaze, Masafumi; Tomoike, Hitonobu; Ueno, K.; Ozawa, Shogo; Sawada, Jun‐ichi

doi:10.2133/dmpk.19.308

Cited by 43 publications

(31 citation statements)

References 14 publications

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“…In the OCT1 gene, all non-synonymous variants except 41Phe > Leu and 117Pro > Leu have already been identified in some racial populations, with a frequency of 0.005-0.81 (Kerb et al 2002;Shu et al 2003). The 41Phe > Leu and 117Pro > Leu allele frequencies were relatively low (0.004), and they have already been reported in a Japanese population (Itoda et al 2004). Recent expression studies have indicated that 341Pro > Leu had decreased ability to transport test compounds, while 160Phe > Leu and 408Met > Val were unchanged (Kerb et al 2002;Sakata et al 2003; Predictive accuracy = 55.5% Shu et al 2003).…”

Section: Discussionmentioning

confidence: 83%

Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin

et al. 2006

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Organic cation transporters (OCTs) are responsible for the hepatic and renal transport of metformin. In this study we analyzed variants of OCT1 and OCT2 genes in 33 patients (24 responders and nine non-responders) based on the hypothesis that polymorphisms in both genes contribute to large interpatient variability in the clinical efficacy of metformin. The sequences of the 5¢-flanking and coding regions of the two genes of interest were screened by singlestrand conformation polymorphism (SSCP) analysis. To compare the causative factors between responders and non-responders, we performed stepwise discriminant functional analysis. Age, body mass index (BMI) and treatment with lipid-lowering agents were demonstrated as positive predictors, and two mutations in the OCT1 gene, -43T > G in intron 1 and 408Met > Val (1222A > G) in exon 7, were negative and positive predictors, respectively, for the efficacy of metformin; the predictive accuracy was 55.5% (P < 0.05). Subsequent study indicated that OCT1 mRNA levels tended to be lower in human livers with the 408Met (1222A) variant, though the differences did not reach the level of significance. In this study it is suggested that OCT1 and OCT2 gene polymorphisms have little contribution to the clinical efficacy of metformin.

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Section: Discussionmentioning

confidence: 83%

Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin

et al. 2006

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“…Selection of OCT1 and OCT3 variants for genotyping was based on two strategies. All variants associated with functional consequences proven by in vitro/in vivo data [29][30][31][32]36,37 were included as well as variants in the 5Ј and 3Ј regions of the OCT1 and OCT3 genes that were available in the National Center for Biotechnology Information database (dbSNP build 127; http://www. ncbi.nlm.nih.gov/sites/entrez?dbϭsnp).…”

Section: Methodsmentioning

confidence: 99%

“…29 In humans, several OCT1 variants with reduced transport function, including metformin transport, have been identified. [29][30][31][32] Some of these variants were recently associated with a significantly decreased glucose-lowering response to metformin and altered metformin pharmacokinetics in healthy volunteers. 29,33 However, in another study, the prevalence of OCT1 variants did not differ between responders and nonresponders to metformin, 34 which may be due to different ethnic study populations or to a small number of subjects in the latter study.…”

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confidence: 99%

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

et al. 2009

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An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrixassisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide singlenucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/ OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113-and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P ‫؍‬ 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.

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“…CYP3A5*3 (6986A4G (rs776746)) and SLC22A1 (156T4C (rs1867351), 480G4C (rs683369), 1022C4T (rs2282143) and 1222A4G (rs628031)) genotyping was performed by PCR-RFLP, as previously described by Fukuen et al 34 and Itoda et al, 25 respectively. Similarly, ABCC2 (À24C4T (rs717620)) and ABCB1 (1236T4C (rs1128503), 2677G4T/A (rs2032582) and 3435T4C (rs1045642)) were genotyped as described by Naesens et al, 35 Wu et al, 36 Tanaka et al 37 and Cascorbi et al, 38 respectively.…”

Section: Measurement Of Plasma Im Concentrationmentioning

confidence: 99%

“…[19][20][21] Although IM is a substrate of OCT1, 15,22,23 no association between IM and SLC22A1 286C4T or 1498G4A, variants not common in the Japanese population, was previously observed. 24,25 In addition, in vitro studies have shown that organic anion-transporting polypeptide 1B3 (OATP1B3), which is encoded by SLCO1B3, contributes to IM uptake into hepatocytes. 24 However, to date, the influence of SLCO1B3 SNPs on the pharmacokinetics of IM has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

et al. 2010

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Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P¼0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P¼0.015). Moreover, previous studies have shown that the ABCG2 421C4A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C4A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

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Seven Novel Single Nucleotide Polymorphisms in the Human SLC22A1 Gene Encoding Organic Cation Transporter 1 (OCT1)

Cited by 43 publications

References 14 publications

Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin

Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

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