Basic study for appropriate use of clinical medicine: functional interaction of drug metabolizing enzymes and its significance in vivo

2015 Fiscal Year Final Research Report

• Project/Area Number: 25293039
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kyushu University
• Principal Investigator: Ishii Yuji 九州大学, 薬学研究科(研究院), 准教授 (90253468)
• Co-Investigator(Renkei-kenkyūsha): YAMADA Hideyuki 九州大学, 大学院薬学研究院, 教授 (40142351)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 薬物代謝 / グルクロン酸抱合 / P450 / UGT / タンパク質間相互作用

Outline of Final Research Achievements

Cumulative evidence suggests that there is protein-protein interaction between cytochromes P450 (P450s, CYPs) and UDP-glucuronosyltransferases (UGTs). In this project, we obtained evidence as follows: 1) The activity of CYP3A4 was significantly suppressed by coexpressing UGT2B7. A series of studies suggested that both hydrophobic domains located near the C terminus and within UGT2B7 are needed for interaction with CYP3A4. 2) CYP3A4 enhances wild-type UGT1A7(*1)-catalyzed glucuronidation. In sharp contrast, CYP3A4 suppresses the activity of UGT1A7*4 that carries a W208R mutation. Therefore, it is suggested that residue 208 of UGT1A7 is crucial for the responsiveness to CYP3A4-dependent modulation. Further, interaction between UGT1A7*1/*4 and CYP3A4 was observed in living cells by fluorescence resonance energy transfer (FRET) analysis. Mutual modulation of UGT and CYP3A4 helps our better understanding of inter-individual differences of CYP3A4 as well as UGT.

Free Research Field

薬物代謝学