Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: In vitro and in vivo studies

Shintani, Masuro

doi:10.1067/mcp.2001.117367

Cited by 81 publications

(65 citation statements)

References 24 publications

(60 reference statements)

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“…Several defective alleles which arise from mutations in this region greatly affect the affinity and catalytic activity of the CYP2C9 enzyme resulting in large variability in dosage requirements of CYP2C9 substrates. [40]These alleles include CYP2C9*3 (I359L) [27], CYP2C9*4 (I359T) (found in Japanese), [41]CYP2C9*5 (D360E) in African-Americans. [31] A Y358C mutation has also been reported to the NCIdbSNP homepage (rs1057909).…”

Section: Discussionmentioning

confidence: 99%

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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Background-Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene.

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Section: Discussionmentioning

confidence: 99%

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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“…Due to the high linkage disequilibrium observed between the 5 0 -flanking region SNPs and the two coding CYP2C9 SNPs, C430T and A1075C, 24 these CYP2C9 haplotypes detected in the population from Galicia could become useful in pharmacogenetic studies as predictors of the interindividual variability in drug response, not explained just by the presence of the coding polymorphisms. This observation also suggests that the pharmacogenetic response associated to CYP2C9 substrates should be evaluated in future studies using more newly described CYP2C9 SNPs of interest.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of CYP2C9 polymorphisms in the south of Europe

et al. 2009

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CYP2C9 is a major liver enzyme responsible of the metabolism of many clinically important drugs. The presence of CYP2C9 genetic polymorphisms has been associated with marked interindividual variability in its catalytic activity that could result in drug toxicity. Here we present frequencies of the most common CYP2C9 coding variants CYP2C9*2 (C430T) and CYP2C9*3 (A1075C) in representative samples of four regions from Spain (Basque Country, n ¼ 358; Catalonia, n ¼ 240; Central Spain, n ¼ 190 and Galicia, n ¼ 288) and one northern Italian region, (Verona, n ¼ 164), which range between 0.125 and 0.165 in the case of CYP2C9*2 and between 0.071 and 0.085 for CYP2C9*3. No significant differences between CYP2C9 allele frequencies were found comparing all the sampled populations. A more extensive comparative analysis using allele frequency data of populations widely spread over Europe was performed, showing significant differences in the CYP2C9*2 allele frequencies distribution between some of the regions, being quite homogeneous in the case of CYP2C9*3 variant. The results obtained show that above 40% of our samples carry a mutate allele, which can result in a poor metabolization of low therapeutic index drugs as oral anticoagulants (warfarin, acenocoumarol), oral antidiabetic drugs and some non-steroidal anti-inflammatory drugs. Our study constitutes both a large (n ¼ 1240) and robust allele frequency database on CYP2C9 polymorphisms, which represents one of the most numerous CYP2C9*2 and *3 database existing to date.

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“…For PHT and CBZ, there are several genetic polymorphisms that have putative or confirmed clinical implications for dosing regimen. First, the initial association between polymorphism in genes for the PHT metabolizing enzyme CYP2C9 and pharmacokinetic parameters of PHT treatment 5,6 has been confirmed. 7 More recent studies provide additional confirmation of influence of CYP2C9 genotype on PHT treatment by showing that patients harboring the *3 allele exhibit a modest (10-15%) but significant reduction in maximum tolerated dose of PHT.…”

Section: Impact Of Pharmacogenetics On Antiepileptic Drug Dosementioning

confidence: 95%

Defining the clinical role of pharmacogenetics in antiepileptic drug therapy

2006

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Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: In vitro and in vivo studies

Abstract: In addition to the two major mutations in the coding region (CYP2C92 and CYP2C93 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.

Cited by 81 publications

References 24 publications

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Prevalence of CYP2C9 polymorphisms in the south of Europe

Defining the clinical role of pharmacogenetics in antiepileptic drug therapy

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Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: In vitro and in vivo studies

Abstract: In addition to the two major mutations in the coding region (CYP2C9*2 and CYP2C9*3 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.

Cited by 81 publications

References 24 publications

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Prevalence of CYP2C9 polymorphisms in the south of Europe

Defining the clinical role of pharmacogenetics in antiepileptic drug therapy

Contact Info

Product

Resources

About

Abstract: In addition to the two major mutations in the coding region (CYP2C92 and CYP2C93 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.