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Associations between CYP2E1 promoter polymorphisms and plasma 1,3-dimethyluric acid/theophylline ratios

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dc.contributor.authorYoon, Yeomin-
dc.contributor.authorPark, Hyung-Doo-
dc.contributor.authorPark, Kyoung Un-
dc.contributor.authorKim, Jin Q-
dc.contributor.authorChang, Yoon-Seok-
dc.contributor.authorSong, Junghan-
dc.date.accessioned2009-11-13T04:16:43Z-
dc.date.available2009-11-13T04:16:43Z-
dc.date.issued2006-
dc.identifier.citationEur J Clin Pharmacol 62:627-631en
dc.identifier.issn0031-6970 (Print)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16841220-
dc.identifier.urihttps://hdl.handle.net/10371/12120-
dc.description.abstractOBJECTIVE: 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 Ins(96), -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 (Ins(96,) -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.en
dc.language.isoen-
dc.publisherSpringer Verlagen
dc.subjectAllelesen
dc.subjectAsthma/metabolismen
dc.subjectCytochrome P-450 CYP1A2/*geneticsen
dc.subjectCytochrome P-450 CYP2E1/*geneticsen
dc.subjectGenotypeen
dc.subjectPharmacogeneticsen
dc.subjectPolymerase Chain Reactionen
dc.subjectPolymorphism, Restriction Fragment Lengthen
dc.subjectTheophylline/blood/*metabolismen
dc.subjectUric Acid/*analogs & derivatives/blooden
dc.subjectPolymorphism, Genetic-
dc.titleAssociations between CYP2E1 promoter polymorphisms and plasma 1,3-dimethyluric acid/theophylline ratiosen
dc.typeArticleen
dc.contributor.AlternativeAuthor윤여민-
dc.contributor.AlternativeAuthor박형두-
dc.contributor.AlternativeAuthor박경운-
dc.contributor.AlternativeAuthor김진규-
dc.contributor.AlternativeAuthor장윤석-
dc.contributor.AlternativeAuthor송정한-
dc.identifier.doi10.1007/s00228-006-0165-4-
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