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人肝脏异喹胍4-羟化酶：对各种单加氧酶底物的特异性测试及活性位点模型

Human liver debrisoquine 4-hydroxylase: test for specificity toward various monooxygenase substrates and model of the active site.

作者信息

Wolff T, Distlerath L M, Worthington M T, Guengerich F P

出版信息

Arch Toxicol. 1987;60(1-3):89-90. doi: 10.1007/BF00296955.

DOI:10.1007/BF00296955
PMID:3619650
Abstract

Polyclonal antibodies raised toward a debrisoquine 4-hydroxylating cytochrome P-450 species purified from rat liver (P-450UT-A) were used to determine which monooxygenase reactions are linked to debrisoquine hydroxylation in human liver. Anti P-450UT-A did not inhibit the oxidation of dimethylnitrosamine, morphine, diazepam, vinylidene chloride, trichloroethylene, benzo(a)pyrene and its 7.8-dihydrodiol, but was inhibitory for the hydroxylation of debrisoquine, (+/-)-bufuralol, lasiocarpine and monocrotaline. A model interpreting the substrate specificity of the human liver enzyme is presented.

摘要

用针对从大鼠肝脏中纯化出的异喹胍4-羟化细胞色素P-450同工酶（P-450UT-A）制备的多克隆抗体，来确定人肝脏中哪些单加氧酶反应与异喹胍羟基化有关。抗P-450UT-A抗体不抑制二甲基亚硝胺、吗啡、地西泮、偏二氯乙烯、三氯乙烯、苯并(a)芘及其7,8-二氢二醇的氧化，但对异喹胍、(±)-布非洛尔、毛果天芥菜碱和野百合碱的羟基化有抑制作用。本文提出了一个解释人肝脏酶底物特异性的模型。

相似文献

1
Human liver debrisoquine 4-hydroxylase: test for specificity toward various monooxygenase substrates and model of the active site.人肝脏异喹胍4-羟化酶：对各种单加氧酶底物的特异性测试及活性位点模型
Arch Toxicol. 1987;60(1-3):89-90. doi: 10.1007/BF00296955.
2
Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling.利用免疫化学抑制和化学建模探究人肝细胞色素P-450异喹胍4-羟化酶的底物特异性。
Cancer Res. 1985 May;45(5):2116-22.
3
Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism.参与异喹胍4-羟化反应的大鼠肝脏微粒体细胞色素P-450的纯化与特性研究，异喹胍是氧化药物代谢遗传变异的一个原型。
Biochemistry. 1984 Jun 5;23(12):2787-95. doi: 10.1021/bi00307a039.
4
Polymorphism of human cytochrome P-450.人类细胞色素P-450的多态性
Xenobiotica. 1987 Mar;17(3):311-6. doi: 10.3109/00498258709043941.
5
A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation.参与异喹胍4-羟化反应的人细胞色素P450底物的三维分子模板。
Carcinogenesis. 1991 Dec;12(12):2211-9. doi: 10.1093/carcin/12.12.2211.
6
Genetic polymorphism in drug oxidation: in vitro studies of human debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase activities.药物氧化中的基因多态性：人异喹胍4-羟化酶和丁呋洛尔1'-羟化酶活性的体外研究
Biochem Pharmacol. 1985 Jan 1;34(1):65-71. doi: 10.1016/0006-2952(85)90101-7.
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Bufuralol 1'-hydroxylase activity of the rat. Strain differences and the effects of inhibitors.大鼠的布呋洛尔1'-羟化酶活性。品系差异及抑制剂的作用。
Biochem Pharmacol. 1986 Sep 1;35(17):2961-5. doi: 10.1016/0006-2952(86)90493-4.
8
Characterization of a rat liver cytochrome P-450UT-H cDNA clone and comparison of mRNA levels with catalytic activity.大鼠肝脏细胞色素P-450UT-H cDNA克隆的鉴定及其mRNA水平与催化活性的比较。
Mol Pharmacol. 1987 Feb;31(2):152-8.
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Bufuralol hydroxylation by cytochrome P450 2D6 and 1A2 enzymes in human liver microsomes.人肝微粒体中细胞色素P450 2D6和1A2酶对布呋洛尔的羟基化作用。
Mol Pharmacol. 1994 Sep;46(3):568-77.
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In vitro evidence against the oxidation of quinidine by the sparteine/debrisoquine monooxygenase of human liver.关于人肝脏中司巴丁/异喹胍单加氧酶对奎尼丁氧化作用的体外证据。
Drug Metab Dispos. 1988 Jan-Feb;16(1):15-7.

引用本文的文献

1
Polymorphisms in oxidative drug metabolism: relationship to food preference.氧化药物代谢中的多态性：与食物偏好的关系。
Br J Clin Pharmacol. 1991 Aug;32(2):235-7. doi: 10.1111/j.1365-2125.1991.tb03887.x.

本文引用的文献

1
Defective oxidation of drugs: pharmacokinetic and therapeutic implications.药物氧化缺陷：药代动力学及治疗学意义
Clin Pharmacokinet. 1982 Jan-Feb;7(1):1-22. doi: 10.2165/00003088-198207010-00001.
2
Characterization of a human liver cytochrome P-450 involved in the oxidation of debrisoquine and other drugs by using antibodies raised to the analogous rat enzyme.通过使用针对类似大鼠酶产生的抗体来鉴定参与异喹胍和其他药物氧化的人肝脏细胞色素P-450。
Proc Natl Acad Sci U S A. 1984 Dec;81(23):7348-52. doi: 10.1073/pnas.81.23.7348.
3
Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism.
参与异喹胍4-羟化反应的大鼠肝脏微粒体细胞色素P-450的纯化与特性研究，异喹胍是氧化药物代谢遗传变异的一个原型。
Biochemistry. 1984 Jun 5;23(12):2787-95. doi: 10.1021/bi00307a039.
4
Lack of relationship between debrisoquine 4-hydroxylation and other cytochrome P-450 dependent reactions in rat and human liver.在大鼠和人肝脏中，异喹胍4-羟化作用与其他细胞色素P-450依赖反应之间缺乏相关性。
Biochem Pharmacol. 1985 Aug 1;34(15):2593-8. doi: 10.1016/0006-2952(85)90553-2.
5
Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling.利用免疫化学抑制和化学建模探究人肝细胞色素P-450异喹胍4-羟化酶的底物特异性。
Cancer Res. 1985 May;45(5):2116-22.
6
Debrisoquine/sparteine-type polymorphism of drug oxidation. Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol.药物氧化的异喹胍/鹰爪豆碱型多态性。参与原型底物布呋洛尔羟化受损的两种功能不同的人肝细胞色素P-450同工酶的纯化与特性鉴定。
J Biol Chem. 1986 Sep 5;261(25):11734-43.
7
Human-liver cytochromes P-450 involved in polymorphisms of drug oxidation.
Xenobiotica. 1986 May;16(5):367-78. doi: 10.3109/00498258609050245.
8
Aldrin epoxidation, a highly sensitive indicator specific for cytochrome P-450-dependent mono-oxygenase activities.艾氏剂环氧化反应，一种对细胞色素P-450依赖的单加氧酶活性具有高度敏感性的特异性指标。
Drug Metab Dispos. 1979 Sep-Oct;7(5):301-5.