Modarai M, Gertsch J, Suter A, Heinrich M, Kortenkamp A
Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK.
J Pharm Pharmacol. 2007 Apr;59(4):567-73. doi: 10.1211/jpp.59.4.0012.
Echinacea preparations are one of the best selling herbal medicinal products with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterization of previously tested preparations. Due to its well characterized immunomodulatory activity, the standardized Swiss registered Echinacea purpurea (L.) Moench Echinaforce extract was selected for detailed study. With the single baculovirus-expressed CYP isoforms 1A2, 2C19, 2D9 and 3A4, inhibitory actions were measured by monitoring fluorescent metabolites derived from enzyme substrates (supersome assay). The Echinaforce extract induced mild inhibition of all these isoforms, with CYP 3A4 being the most, and CYP 2D6 the least sensitive enzyme. To assess whether CYP inhibition might be a general feature of Echinacea preparations, an additional nine commercially available preparations were screened using CYP 3A4. All tested preparations were able to inhibit CYP 3A4, but inhibitory potencies (expressed as median inhibitory concentration, IC50) varied by a factor of 150. The alkylamides are thought to be responsible for the immunomodulatory activity of Echinacea, and so the concentration of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations, and the latter was found to be associated with their CYP 3A4 inhibitory potency. The chemically pure alkylamides dodeca-2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and dodeca-2E,4E-dieonoic acid isobutylamide (2) showed inhibitory activity on CYP 2C19, 2D6 and 3A4. However, unlike the Echinaforce extract, the alkylamides did not induce CYP 1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in-vitro.
紫锥菊制剂是最畅销的草药产品之一，在预防上呼吸道感染方面有确切的治疗用途。其消费量正在增加，但关于它们抑制细胞色素P450酶（CYP）能力的信息并不完整。由于之前测试的制剂缺乏植物化学特征描述，情况变得更加复杂。由于其具有明确的免疫调节活性，选择了瑞士注册的标准化紫锥菊提取物Echinaforce进行详细研究。使用单一杆状病毒表达的CYP同工型1A2、2C19、2D9和3A4，通过监测酶底物衍生的荧光代谢物（超微粒体测定）来测量抑制作用。Echinaforce提取物对所有这些同工型均有轻度抑制作用，其中CYP 3A4最敏感，CYP 2D6最不敏感。为了评估CYP抑制是否可能是紫锥菊制剂的一个普遍特征，使用CYP 3A4对另外九种市售制剂进行了筛选。所有测试制剂均能抑制CYP 3A4，但抑制效力（以半数抑制浓度，IC50表示）相差150倍。烷基酰胺被认为是紫锥菊免疫调节活性的原因，因此测定了所有制剂中2E,4E,8Z,10E/Z-四烯酸异丁酰胺（1）的浓度和总烷基酰胺含量，发现后者与其CYP 3A4抑制效力有关。化学纯的烷基酰胺十二碳-2E,4E,8Z,10E/Z-四烯酸异丁酰胺（1）和十二碳-2E,4E-二烯酸异丁酰胺（2）对CYP 2C19、2D6和3A4有抑制活性。然而，与Echinaforce提取物不同，烷基酰胺并未诱导CYP 1A2抑制。因此，其他尚未鉴定的成分也导致了紫锥菊制剂在体外观察到的总体微弱抑制作用。
