| Project/Area Number |
17590128
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 UNIVERCITY |
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Principal Investigator |
ISHII Yuji Kyushu University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究院, 助教授 (90253468)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | drug metabolism / UGT / P450 / adenine / protein-protein interaction / endogenous small compound / morphine / cross-linking / シトクロムP450 / UDP-グルクロン酸転移酵素 / 架橋 / 免疫沈降 |
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| Research Abstract |
Post-translational modulation of activities of drug-metabolizing enzymes was studied. Followings are outcomes from this project. 1) CYP1A2 and CYP2C9 have ability to modify UGT2B7 function. However, the mechanism(s) underlying the modulation of UGT2B7 function by these P450s seems to differ from that by CYP3A4. 2) CYP3A4-UGT2B7 association was demonstrated in more detail by means of immunoprecipitation, overlay assay and cross-linking with a cross-linker, 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide (EDC). 3) The candidate region of CYP3A4 which plays a role in the interaction with UGT2B7 was determined. 4) Ketoconazole exerts its inhibitory effect on morphine UGT by novel mechanisms involving competitive and noncompetitive inhibition. 5) P450-UGT association was also found in rats. It was suggested that such interaction is conserved from species to species. 6) Acyl-CoAs play a role as an endogenous activator of UGTs. 7) A number of cellular nucleotides present within the endoplasmic reticulum regulate UGT function. Further these substances bind to a common allosteric site on UGT to reduce catalytic function.
These results suggest that there are functional interaction between P450 and UGT. In addition, endogenous modulators may also important for UGT. Further study is necessary to clarify the impact of interaction between CYP3A4 and UGT2B7 on UGT2B7-catalyzed reaction in vivo.
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