Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity
Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity
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DOI：
10.1016/s0024-3205(99)00407-5
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发表时间：
1999-09-03
期刊：
影响因子：
6.1
通讯作者：
Stresser, DM
中科院分区：
文献类型：
--
作者：
Henderson, GL;Harkey, MR;Stresser, DM
由于草药产品与标准药物之间的相互作用知之甚少，我们在体外实验中研究了7种人参皂苷和2种刺五皂苷（人参根的活性成分）对c-DNA表达的细胞色素P450异构体的催化活性的影响。将人参皂苷Rb1、Rb2、Re、Rd、Re、Rf和Rg1浓度的增加以及栀子苷B和E与一组重组人CYP同种异构体（CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4）一起孵育，并在96孔板上用荧光法测量它们对特定替代底物转化的影响。对于每种测试物质，估计IC50（抑制替代底物代谢50%所需的浓度），并将该值与阳性对照抑制药物呋喃茶碱、磺胺苯唑、tryanyylcypromine、奎尼丁和酮康唑的值进行比较。在测试的成分中，三种人参皂苷（Rd， Re和Rf）修饰了重组酶的活性。人参皂苷Rd对CYP3A4和CYP2D6代底物的抑制活性较弱，对CYP2C19和CYP2C9代底物的抑制活性更弱。CYP3A4的两种底物的IC50值分别为58和74 uM，比作为阳性对照的强效抑制剂酮康唑的IC50值高几个数量级。人参皂苷Re使CYP2C9活性增加（在200 uM时增加70%），人参皂苷Rf使CYP3A4活性增加（在200 uM时增加54%）。这在生物学上的意义目前还不清楚。酶的“活化”，即直接将一种化合物添加到酶中以提高底物的反应速率的过程，已经在P450酶的许多情况下被观察到；然而，不能排除由与标记底物的代谢物在相同波长上发出荧光的测试化合物引起的基质效应。总之，这些研究表明，人参皂苷和刺五皂苷不太可能抑制共给药的代谢，其中主要的消除途径是通过细胞色素P450；人参皂苷增强某些底物催化作用的潜力有待进一步研究。(C) 1999 Elsevier Science Inc.；
Because little is known about the interactions between herbal products and standard medications, the effects of seven ginsenosides and two eleutherosides (active components of the ginseng root) on the catalytic activity of c-DNA expressed cytochrome P450 isoforms were studied in in vitro experiments. Increasing concentrations of ginsenosides Rb1, Rb2, Re, Rd, Re, Rf, and Rg1 and eleutherosides B and E were incubated with a panel of recombinant human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their effects on the conversion of specific surrogate substrates measured fluorometrically in a 96-well plate format. For each test substance, the IC50 (the concentration required to inhibit the metabolism of the surrogate substrates by 50%) was estimated and this value compared with that obtained for positive control inhibitory drugs furafylline, sulfaphenazole, tryanylcypromine, quinidine, and ketoconizole. Of the components tested, three ginsenosides (Rd, Re, and Rf) modified the activity of the recombinant enzymes. Ginsenoside Rd produced weak inhibitory activity against the surrogate substrates for CYP3A4 and CYP2D6 and even weaker inhibitory activity against the surrogate substrates for CYP2C19 and CYP2C9. The IC50 values of 58 and 74 uM for the two substrates for CYP3A4 are orders of magnitude higher than that for the potent inhibitor ketoconazole used as a positive control. Ginsenoside Re produced an increase in the activity of CYP2C9 (70% at 200 uM) and ginsenoside Rf produced an increase in the activity of CYP3A4 (54% at 200 uM). The biological significance of this is unclear at this time. Enzyme "activation", the process by which direct addition of one compound to an enzyme enhances the rate of reaction of the substrate, has been observed in a number of cases with P450 enzymes; however, a matrix effect caused by the test compound fluorescing at the same wavelength as the metabolite of the marker substrate cannot be ruled out. In summary, these studies suggest that the ginsenosides and eleutherosides tested are not likely to inhibit the metabolism of coadministered medications in which the primary route of elimination is via cytochrome P450; the potential of ginsenosides to enhance the catalysis of certain substrates requires further investigation. (C) 1999 Elsevier Science Inc.