2004 Fiscal Year Final Research Report Summary
Evidence for functional interaction between phase I and phase II drug metabolizing enzymes
| Project/Area Number |
14370765
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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 |
Environmental pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
YAMADA Hideyuki Kyushu University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究院, 教授 (40142351)
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| Co-Investigator(Kenkyū-buntansha) |
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) |
2002 – 2004
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| Keywords | functional protein-protein interaction / cytochrome P450 / UDP-glucuronosyltransferase / morphine |
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| Research Abstract |
Functional protein-protein interaction between phase I and phase II drug metabolizing enzymes was studied. While many cytochrome P450 (P450) enzymes associate nonspecifically with microsomal epoxide hydrolase (mEH), the CYP2C11 plays a greater role in the association/activation of mEH. In addition, P450-mediated activation of mEH depends upon the substrate of mEH. Thus, protein-protein interaction between P450 and mEH modulates mEH function. On the other hand, a UGT isoform(s) involved in 3-hydroxybenzo(a)pyrene glucuronidation is interfered by a CYP1A inhibitor, alpha-naphthoflavone via a mechanism dependent on the intact nature of microsomal membranes in 3-methyl-cholanthrene-treated rats. It is likely that P450 functions as a substrate supplier for some isoforms of UGT via possible interactions between UGT and P450. Further, a major human P450, CYP3A4 interacts with and modulates UGT2B7-catalyzed morphine glucuronidation. CYP3A4 alters UGT2B7 regioselectivity so that the ratio of morphine activation/detoxication is increased. This study provides the first evidence that P450 is not only involved in oxidation of drugs but also modulates the function of UGTs. Functional interaction between drug metabolizing enzymes may finely tune to eliminate various kinds of drugs and environmental pollutants.
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