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 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.
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 asthmapatients. 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.
Authors: N Hanioka; T Tanaka-Kagawa; Y Miyata; E Matsushima; Y Makino; A Ohno; R Yoda; H Jinno; M Ando Journal: Xenobiotica Date: 2003-06 Impact factor: 1.908
Authors: Y Tanigawara; F Komada; T Shimizu; S Iwakawa; T Iwai; H Maekawa; R Hori; K Okumura Journal: Biol Pharm Bull Date: 1995-11 Impact factor: 2.233