Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions

Sakata, Toshiie; Anzai, Naohiko; Shin, Ho Jung; Noshiro, Rie; Hirata, Terumitsu; Yokoyama, Hirokazu; Kanai, Yoshikatsu; Endou, Hitoshi

doi:10.1016/j.bbrc.2003.11.175

Cited by 98 publications

(65 citation statements)

References 23 publications

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“…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). Interestingly, the 341Pro > Leu variant was observed in Asian and African American populations but not in Caucasians (Shu et al 2003); however, there was no difference in the allele frequency of 341Pro > Leu between responders and nonresponders to metformin therapy in this study.…”

Section: Discussionmentioning

confidence: 74%

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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: 74%

“…Recently, a number of single nucleotide polymorphisms (SNPs) has been identified in the OCT1 gene. Some of these SNPs have been found to be associated with altered in vitro transport activity (Hundal et al 2000;Sakata et al 2003;Shu et al 2003;Takeuchi et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…Several genetic variants of OCT1 and OCT3 with impaired transport function in vitro have been described so far (Table 3), [29][30][31]37,51,52 and interestingly, some of them have already been associated with altered metformin pharmacokinetics. 33 Comprehensive genotyping of 92 variants in the OCT1-3 gene cluster by MALDI-TOF MS and Illumina DNA chip technology revealed the occur- rence of 10 nonsynonymous variants (nine in OCT1 and one in OCT3) in our population of 150 Caucasian subjects (Table 3, Supporting Table 5) with allele frequencies corresponding to those published for northern/western European populations.…”

Section: Discussionmentioning

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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“…34,35 In addition, polymorphisms within OCT-1 have been shown to affect transporter function. [36][37][38] Hence, functional Activity of the OCT-1 protein may be more relevant for patient response than OCT-1 mRNA expression.…”

Section: Oct-1 Mrnamentioning

confidence: 99%

Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity

et al. 2010

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Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions

Cited by 98 publications

References 23 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

Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity

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