2007 Fiscal Year Final Research Report Summary
The role of allelic expression imbalance (AER) in interindividual differences in CYP3A4 activity and it's clinical implications.
| Project/Area Number |
17390043
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
IEIRI Ichiro Kyushu University, Graduate School of Pharmaceutical Sciences, Associate Professor (60253473)
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| Co-Investigator(Kenkyū-buntansha) |
OTSUBO Kenji Tottori University, Hospital, Pharmacy, Professor (80260701)
NANBA Eiji Tottori University, Research Center for Bioscience and Technology, Professor (40237631)
BURIOKA Naoto Tottori University, Hospital, Internal Medicine, Associate (50252854)
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| Project Period (FY) |
2005 – 2007
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| Keywords | CYP3A4 / CYP3A5 / allelic expression imbalance / epigenetics / midazolam / itraconazole / clinical study |
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| Research Abstract |
(1) Development of conventional assay kit for the allelic expression ratio (AER) A single nucleotide polymorphism (SNP), T/T-deletion, position at 88742 in human CYP3A4 gene is used for the marker Serial dilution standard samples using DNAs (i e, homozygous for each allele) were used for the calibration Correlation between allelic ratio and fluorescence intensity (VIC / FAM) was excellent We developed conventional assay kit for AER in the CYP3A4 gene using TaqMan primers and probe sets.
(2) Clinical Application Using this assay kit, we evaluated relationship between individual AER and metabolic activities of midazolam and itraconazole in Japanese healthy volunteers Unfortunately, due to the small sample sizes, clear relationships were not observed Since individual AER was estimated successfully, a larger sample size study using more specific substrate drugs for CYP3A4 is warranted.
(3) Methylation analysis There are various CpG islands in the imprinting control center (ICR), ICR is located on the upstream of human CYP3A4 gene When we focused on 4 CG sites at position 82363 to 82893, methylation frequencies at 14th and 16th CG sites negatively correlated with the CYP3A4 m RNA expression levels at significantly.
(4) Histone acetylation 5'-upstream and 3'-downstream regions, 5'-UTR, and promoter regions of the CYP3A4 gene were selected as targets Large interindividual differences in the anti-Ac-H3 binding capacity were observed in various target regions, histone acetylation in 5'-upstream regions of CYP3A4 was significantly correlated with mRNA expression.
(5) Methylation status and Histone acetylation Methylation frequencies in above mentioned 4 CG sites were significantly correlated with histone acetylation at approximately 2000 bp upstream of the CYP3A4 gene These results suggest that DNA methylation in the ICR involved in the histone acetylation at the upstream of the CYP3A4 gene, leading to cis-acting phenomenon, allelic expression imbalance.
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Research Products
(12 results)
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[Journal Article] Ieiri I : Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy2006
Author(s)
Takane, H., Miyata, M., Burioka, N., Shigemasa, C., Shimizu, E., Otsubo, K
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Journal Title
J Hum Genet 51
Pages: 822-886
Description
「研究成果報告書概要(欧文)」より
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[Book] 分子薬物動態学2008
Author(s)
家入 一郎(分担)
Total Pages
690
Publisher
南山堂
Description
「研究成果報告書概要(和文)」より
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