Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes

• Published in: European journal of clinical pharmacology Vol. 68; no. 7; pp. 1033 - 1042
• Main Authors: Hatta, Fazleen H. M., Teh, Lay Kek, Helldén, Anders, Hellgren, Karin Engström, Roh, Hyung-Keun, Salleh, Mohd Zaki, Aklillu, Eleni, Bertilsson, Leif
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2012; Springer; Springer Nature B.V
• Subjects: Adult; Alleles; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Asian Continental Ancestry Group; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cytochrome P-450 CYP2C9; Data Interpretation, Statistical; Drugs; Ethnicity; European Continental Ancestry Group; Exons - genetics; Genetics; Haplotypes; Humans; Introns - genetics; Losartan - metabolism; Losartan - pharmacokinetics; Male; Medical sciences; Medicin och hälsovetenskap; Metabolic Detoxication, Phase I; Metabolism; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phenotype; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Republic of Korea; Sweden; Young Adult; Sweden; Asia; Europe; Korea; Republic of Korea; Haplotypes; CYP2C9; Losartan; Metabolic ratio; Phenytoin ultra-rapid metaboliser; Koreans; Swedes; Imidazole derivatives; Tetrazole derivatives; Isozyme; Peptide hormone; Pharmacotherapy; Non peptide compound; Anticonvulsant; Octapeptide; Angiotensin II; Haplotype; Human; Drug; Enzyme; Cytochrome P450; Metabolism; Renin angiotensin system; Phenotype; Treatment; Biphenyl derivatives; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; Pharmacokinetics; Molecular biology; Phenytoin; CYP2C9 gene
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-012-1210-0

Aim To search for a relationship between ultra-rapid metabolism catalysed by cytochrome P450 2C9 (CYP2C9) and its genotypes. 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 . Results We found a significant relationship between SNP 4 (IVS8-109A>T) and CYP2C9 activity (χ 2 -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 ( p  = 0.001) 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 the MR was generally higher among the Swedes compared to the Koreans (Mann–Whitney test, p  < 0.05). 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.