Evidence for functional interaction between phase I and phase II drug metabolizing enzymes

I 期和 II 期药物代谢酶之间功能相互作用的证据

• 批准号: 14370765
• 负责人: YAMADA Hideyuki
• 金额: $ 6.66万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370765/
• 关键词: functional protein-protein interaction; cytochrome P450; UDP-glucuronosyltransferase; morphine; Cytochrome P450; UDP-Glucuronosyltransferase; RNAi; 免疫沈降; 共発現; Kinetics

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.

研究了I相和II相药物代谢酶之间的功能性蛋白质-蛋白质相互作用。虽然许多细胞色素P450（P450）酶与微粒体环氧化物水解酶（mEH）非特异性相关，但CYP 2C 11在mEH的相关/激活中发挥更大作用。此外，P450介导的mEH激活依赖于mEH的底物。因此，P450和mEH之间的蛋白质-蛋白质相互作用调节mEH功能。另一方面，参与3-羟基苯并（a）芘葡萄糖醛酸化的UGT亚型通过依赖于3-甲基胆蒽处理大鼠中微粒体膜完整性质的机制受到CYP 1A抑制剂α-萘啶酮的干扰。P450可能通过UGT和P450之间可能的相互作用作为UGT某些亚型的底物供应者。此外，主要的人P450，CYP 3A 4与UGT 2B 7催化的吗啡葡萄糖醛酸化相互作用并调节。CYP 3A 4改变UGT 2B 7的区域选择性，从而增加吗啡活化/解毒的比率。本研究首次证明P450不仅参与药物的氧化，而且还调节UGT的功能。药物代谢酶之间的功能相互作用可以进行微调以消除各种药物和环境污染物。

项目成果

Cytochrome P450 1A1(CYP1A1) inhibitor a-naphthoflavone interferes with UDP-glucuronosyl-transferase(UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methyl-cholanthrene-treated rats : possible involvement of UGT-P450 interactions

细胞色素 P450 1A1(CYP1A1) 抑制剂 α-萘黄酮干扰 UDP-葡萄糖醛酸基转移酶 (UGT) 活性，但不干扰 3-甲基胆蒽处理大鼠的透化肝微粒体：可能涉及 UGT-P450 相互作用

• 发表时间: 2004
• 期刊: Biological and Pharmaceutical Bulletin 27・1
• 作者: Taura;K.;他5名
• 通讯作者: 他5名

Modulation of UDP-glucuronosyltransferase function by cytochrome P450: Evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4

• DOI: 10.1124/mol.104.007641
• 发表时间: 2005-03-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Takeda, S;Ishii, Y;Yamada, H
• 通讯作者: Yamada, H

Taura, K., et al.: "Cytochrome P4501A1 (CYP1A1) inhibitor α-naphthoflavone interferes with UDP-glu-curonosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats : possible involvement of U

Taura, K. 等人：“细胞色素 P4501A1 (CYP1A1) 抑制剂 α-萘黄酮会干扰完整的 UDP-葡萄糖醛酸基转移酶 (UGT) 活性，但不会干扰 3-甲基胆蒽处理大鼠的透化肝微粒体：可能涉及 U

Modulation of UDP-glucuronosyltransferase function by cytochrome P450 : evidence forthe alteration of UGT2B7-catalyzed blucuronidation of morphine by CYP3A4

细胞色素 P450 对 UDP-葡萄糖醛酸基转移酶功能的调节：CYP3A4 改变 UGT2B7 催化的吗啡糖醛酸化的证据

• 发表时间: 2005
• 期刊: Molecular Pharmacology 67・2
• 作者: Takeda;S.;他7名
• 通讯作者: 他7名

Cytochrome P450 1A1 (CYP1A1) inhibitor α-naphthoflavone interferes with UDP-glucuronosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats : possible involvement of UGT-P450 interactions

细胞色素 P450 1A1 (CYP1A1) 抑制剂 α-萘黄酮干扰完整的 UDP-葡萄糖醛酸基转移酶 (UGT) 活性，但不干扰 3-甲基胆蒽处理大鼠的透化肝微粒体：可能涉及 UGT-P450 相互作用

• 发表时间: 2004
• 期刊: Biol Pharm Bull 27
• 作者: Taura K;Naito E;Ishii Y;Mori M;Oguri K;Yamada H
• 通讯作者: Yamada H