Abstract
Objective
Theophylline is metabolized to 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine, and 1-methylxanthine by CYP1A2 and partly by CYP2E1. Because 1,3-DMU is the major metabolite of theophylline, the 1,3-DMU/theophylline ratio is viewed as a good indicator of theophylline metabolic clearance. Here, we investigated the associations between 1,3-DMU/theophylline ratios and genetic polymorphisms of CYP2E1 and CYP1A2.
Methods
Polymerase chain reaction (PCR) and direct sequencing or PCR-restriction fragment length polymorphism (RFLP) were performed to analyze CYP2E1 and CYP1A2 promoter polymorphisms in 62 Korean asthma patients. Plasma theophylline and 1,3-DMU levels were measured by liquid chromatography-tandem mass spectrometry.
Results
Eleven polymorphisms including Ins96, −1566 T>A, −1515 T>G, −1414 C>T, −1295 G>C, −1055 C>T, −1027 T>C, −930 A>G, −807 T>C, −352 A>G, and −333 T>A were detected in the 5′ flanking region of the CYP2E1 gene (numbering according to GenBank Accession number NT_017795). Of these, five single nucleotide polymorphisms (SNPs) (−1566 T>A, −1295 G>C, −1055 C>T, −1027 T>C, and −807 T>C) were closely linked. Another three polymorphisms (Ins96, −930 A>G, and −352 A>G) and two polymorphisms (−1515 T>G and −333 T>A) were also closely linked. The five closely linked polymorphisms were associated with significantly different 1,3-DMU/theophylline ratios between heterozygotes plus homozygotes of a rare allele (n=23, 0.0368±0.0171) and common allelic homozygotes (n=39, 0.0533±0.0343) (p=0.024 by Mann-Whitney U test). In the CYP1A2 gene, the −2964G>A polymorphisms exhibited a significant difference in 1,3-DMU/theophylline levels between heterozygotes plus homozygotes of a rare allele (n=30, 0.0406±0.0272) and homozygotes of a common allele (n=32, 0.0534±0.0316) (p=0.032).
Conclusion
We confirm that hydroxylation at the 8 position of theophylline (1,3-DMU) is significantly affected by genetic polymorphism in CYP2E1 in addition to CYP1A2.
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Acknowledgements
This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, R.O.K(03-PJ10-PG13-GD01-0002).
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Yoon, Y., Park, HD., Park, K.U. et al. Associations between CYP2E1 promoter polymorphisms and plasma 1,3-dimethyluric acid/theophylline ratios. Eur J Clin Pharmacol 62, 627–631 (2006). https://doi.org/10.1007/s00228-006-0165-4
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DOI: https://doi.org/10.1007/s00228-006-0165-4