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Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes.
- Source :
-
European journal of clinical pharmacology [Eur J Clin Pharmacol] 2012 Jul; Vol. 68 (7), pp. 1033-42. Date of Electronic Publication: 2012 Feb 01. - Publication Year :
- 2012
-
Abstract
- Aim: To search for a relationship between ultra-rapid metabolism catalysed by cytochrome P450 2C9 (CYP2C9) and its genotypes.<br />Methods: DNA from a Swedish ultra-rapid metaboliser patient [losartan metabolic ratio (MR) <0.13] and three healthy Swedes with normal CYP2C9 activity and a MR of about 1 were assessed for variation in the CYP2C9 gene. Direct DNA sequencing was performed for all exons and exon-intron junctions and also for -2100 bp of the 5′-flanking regions of the CYP2C9 gene. This analysis revealed four intronic mutations [single nucleotide polymorphisms (SNPs) 1-4] in the three samples with normal MR while no variation was observed in the ultra-rapid metaboliser. PCR/restriction fragment length polymorphism and allele-specific PCR methods were subsequently developed to screen 85 Swedes and 128 Koreans without CYP2C9*2 or *3.<br />Results: We found a significant relationship between SNP 4 (IVS8-109A>T) and CYP2C9 activity (χ²-test, p=0.011) in the Swedes. Twenty Swedes with the lowest MR were compared with 20 Swedes with the highest MR, revealing a strong association (p00.001) between SNP4 and higher MR. For homozygous SNP 1 (IVS1+83T>C), SNP 2 (IVS2+73T>C), and SNP 3 (IVS6+95A>G), no phenotype and genotype relationships were found, but theMRwas generally higher among the Swedes compared to the Koreans (Mann-Whitney test, p<0.05).<br />Conclusions: We found that the SNP 4 IVS8-109T allele is associated with a higher CYP2C9 MR in healthy Swedish subjects, but further investigations need to be carried out to establish a molecular explanation for ultra-rapid CYP2C9- catalysed metabolism. Haplotype based on SNPs 1-4 did not seem to contribute to variation in the MR of the Korean subjects nor play a role in determining the MR of the Swedish ones.
- Subjects :
- Adult
Alleles
Cytochrome P-450 CYP2C9
Data Interpretation, Statistical
Exons genetics
Haplotypes
Humans
Introns genetics
Losartan pharmacokinetics
Male
Metabolic Detoxication, Phase I
Phenotype
Polymerase Chain Reaction
Polymorphism, Restriction Fragment Length
Republic of Korea
Sweden
Young Adult
Aryl Hydrocarbon Hydroxylases genetics
Aryl Hydrocarbon Hydroxylases metabolism
Asian People
Losartan metabolism
Polymorphism, Single Nucleotide
White People
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1041
- Volume :
- 68
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- European journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22294058
- Full Text :
- https://doi.org/10.1007/s00228-012-1210-0