Investigation of cytochrome P450 inhibitory properties of maslinic acid, a bioactive compound from Olea europaea L., and its structure-activity relationship
Investigation of cytochrome P450 inhibitory properties of maslinic acid, a bioactive compound from Olea europaea L., and its structure-activity relationship
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DOI：
10.1016/j.phymed.2014.10.003
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发表时间：
2015-01-15
期刊：
影响因子：
7.9
通讯作者：
Wang, Xin
中科院分区：
文献类型：
--
作者：
Sun, Min;Tang, Yu;Wang, Xin
山楂酸（Maslinic acid，MA）是油橄榄（Olea europueo L.）水果具有多种药理作用，包括降血糖、抗氧化、心脏保护和抗肿瘤活性。尽管它的重要性，很少有人知道它对细胞色素P450（CYP 450）在人类和动物的活动的影响。因此，本研究的目的是研究MA对人和大鼠肝微粒体和特异性β 1受体亚型的β 1A 2、2C 9/11、2D 1/6、2 E1和3A 2/4活性的影响。在人体中，MA仅对人肝微粒体和特异性CYP 3A 4亚型中的CYP 3A 4活性有微弱抑制作用，IC 50值分别为46.1和62.3 μ M。在大鼠中，MA对CYP 2C 11、CYP 2 E1和CYP 3A 2活性也表现出弱抑制作用，IC 50值大于100 μ M。酶动力学研究表明，MA不仅是人CYP 3A 4的竞争性抑制剂，而且是大鼠CYP 2C 11和3A 2的竞争性抑制剂，Ki分别为18.4、93.7和66.3 μ M。此外，与油酸相比，MA中三萜酸C-2位羟基的存在可放大其对人CYP 3A 4活性的竞争性抑制。MA相对较高的Ki值导致可能的毒性和药物相互作用的可能性较低，涉及酶，因此表明其作为与药物一起服用的营养品的假定用途具有足够的安全性。(C)2015 Elsevier GmbH. All rights reserved.
Maslinic acid (MA), the main pentacyclic triterpene of Olea europueo L. fruit, possesses a variety of pharmacological actions, including hypoglycemic, antioxidant, cardioprotective and antitumoral activities. Despite its importance, little is known about its effects on the cytochrome P450 (CYP) activity in both humans and animals. Therefore, the aim of this study was to investigate the effects of MA on the CYP 1A2, 2C9/11, 2D1/6, 2E1 and 3A2/4 activities by human and rat liver microsomes and specific CYP isoforms. In humans, MA only weakly inhibited CYP3A4 activity in human liver microsomes and specific CYP3A4 isoform with IC50 value at 46.1 and 62.3 mu M, respectively. In rats, MA also exhibited weak inhibition on CYP2C11, CYP2E1 and CYP3A2 activities with IC50 values more than 100 mu M. Enzyme kinetic studies showed that the MA was not only a competitive inhibitor of CYP3A4 in humans, but also a competitive inhibitor of CYP2C11 and 3A2 in rats, with K-i of 18.4, 93.7 and 66.3 mu M, respectively. Moreover, the presence of hydroxyl group at C-2 position of triterpenic acid in MA compared with oleanolic acid could magnify its competitive inhibition on human CYP3A4 activity. The relatively high K-i values of MA would have a low potential to cause the possible toxicity and drug interactions involving CYP enzymes, thus suggesting a sufficient safety for its putative use as a nutraceutical taken together with drugs. (C) 2015 Elsevier GmbH. All rights reserved.