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1. Eur J Clin Pharmacol. 2012 Feb 1. [Epub ahead of print]

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

Hatta FH, Teh LK, Helldén A, Hellgren KE, Roh HK, Salleh MZ, Aklillu E,
Bertilsson L.

Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska
Institutet-Karolinska University Hospital, Huddinge, 141 86, Stockholm, Sweden,

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.

PMID: 22294058 [PubMed - as supplied by publisher]