| Budget Amount *help |
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2013: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
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| 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.
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