超声对大鼠肝脏药物代谢酶的抑制作用及肝素的纠正作用。

Inhibition of enzymes of drug metabolism in rat liver by ultrasound and correction by heparin.

作者信息

Legonkova L F, Bushma M I, Zverinsky I V, Eismont K A

机构信息

Institute of Biochemistry, National Academy of Sciences, Grodno, Belarus.

出版信息

Exp Toxicol Pathol. 1999 Jul;51(4-5):360-2. doi: 10.1016/S0940-2993(99)80022-0.

DOI:10.1016/S0940-2993(99)80022-0

PMID:10445398

Abstract

After 6 days following the local effect (during operation) of ultrasound (2 Wt/cm2, 1 min) the microsomal fraction showed decreased total content of cytochromes P-450 (P-450), rate of NADPH oxidation, activity of NADPH-cytochrome P450 reductase and P450 IIE1 (aniline as substrate) by 40, 28, 16 and 42 %, respectively. In addition, after 12 days the activities of P450 IIIA1 (ethylmorphine as substrate) and cytosolic sulphobromophthalein glutathione transferase (SBPh-GT) were decreased by 59 and 26 %. The administration of heparin (intramuscularly, 250 ED/kg, in a day, 3 and 6 times) exerted a normalizing effect. The P450 concentration, NADPH oxidation rate and P450 IIB1 activity (amidopyrine as substrate), IIE1 and IIIA1, SBPh-GT and 1-chloro-2,4-dinitrobenzene-GT in microsomes and cytosol exceeded the corresponding values in untreated animals by 31, 40, 68, 224, 68, 42, 24 and 36 %. The administration of heparin to control animals (intramuscularly, 250 and 500 mg/kg, in a day, 5 times) essentially unaffected both the monooxygenase, glucuro- and glutathione-conjugating systems and the elimination of antipyrine (substrate of preferably P-450 IA2) and SBPh (substrate of GT) from rat blood plasma. The experimental results provide evidence for a possible role of endogenous heparin in maintaing the optimal level of the activities of the enzyme systems of xenobiotics microsomal oxidation and conjugation in liver injury. One of the most important functions of the liver is its ability to execute biotransformation of a wide range of xenobiotics and some endogenous substances [1]. The activities of the enzyme systems catalyzing these reactions are under a sophisticated regulatory control. Among the natural factors capable of changing the function of enzymes involved in the xenobiotic biotransformation are vitamins [2], phospholipids [3], hormones [4] and many others. We studied the effect of heparin on the activities of the monooxygenase, glucuro- and glutathione transferase systems of the intact and ultrasound-treated rat liver. The significance of this study consists in the elucidation of a putative participation of heparin in the control of the activities of the enzyme system of xenobiotic biotransformation in the intact liver and under membranous pathology of the organ.

摘要

在超声（2瓦/平方厘米，1分钟）产生局部效应（手术期间）6天后，微粒体部分显示细胞色素P - 450（P - 450）的总含量、NADPH氧化速率、NADPH - 细胞色素P450还原酶和P450 IIE1（以苯胺为底物）的活性分别降低了40%、28%、16%和42%。此外，12天后，P450 IIIA1（以乙基吗啡为底物）和胞质磺溴酞谷胱甘肽转移酶（SBPh - GT）的活性分别降低了59%和26%。注射肝素（肌肉注射，250 ED/千克，每天1次，共3次和6次）发挥了归一化作用。微粒体和胞质中的P450浓度、NADPH氧化速率以及P450 IIB1活性（以氨基比林为底物）、IIE1和IIIA1、SBPh - GT以及1 - 氯 - 2,4 - 二硝基苯 - GT超过未处理动物的相应值，分别为31%、40%、68%、224%、68%、42%、24%和36%。给对照动物注射肝素（肌肉注射，250毫克/千克和500毫克/千克，每天1次，共5次）基本上未影响单加氧酶、葡萄糖醛酸和谷胱甘肽结合系统，也未影响大鼠血浆中安替比林（P - 450 IA2的优选底物）和SBPh（GT的底物）的消除。实验结果证明内源性肝素在肝损伤中维持外源性微粒体氧化和结合酶系统活性的最佳水平方面可能发挥作用。肝脏最重要的功能之一是其对多种外源性物质和一些内源性物质进行生物转化的能力[1]。催化这些反应的酶系统的活性受到复杂的调节控制。在能够改变参与外源性物质生物转化的酶功能的天然因素中，有维生素[2]、磷脂[3]、激素[4]等许多因素。我们研究了肝素对完整和经超声处理的大鼠肝脏的单加氧酶、葡萄糖醛酸和谷胱甘肽转移酶系统活性的影响。本研究的意义在于阐明肝素在完整肝脏以及器官膜性病理状态下对外源性物质生物转化酶系统活性控制中的假定参与情况。