Sasaki Takamitsu, Sato Yu, Kumagai Takeshi, Yoshinari Kouichi, Nagata Kiyoshi
Department of Environmental and Health Science, School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558 Japan.
Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan.
J Pharm Health Care Sci. 2017 May 10;3:14. doi: 10.1186/s40780-017-0083-x. eCollection 2017.
Health foods have been widely sold and consumed in Japan. There has been an increase in reports of adverse effects in association with the expanding health food market. While health food-drug interactions are a particular concern from the viewpoint of safe and effective use of health foods, information regarding such interactions is limited owing to the lack of established methods to assess the effects of health food products on drug metabolism. We therefore developed cells that mimicked the activities of cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4, which strongly contribute to drug metabolism in human hepatocytes, and established a system to assess the inhibitory activity of health foods toward P450-mediated metabolism.
We simultaneously infected HepG2 cells with five P450-expressing adenoviruses (Ad-CYP1A2, Ad-CYP2C9, Ad-CYP2C19, Ad-CYP2D6, and Ad-CYP3A4) to mimic the activity levels of these P450s in human hepatocytes, and named them Ad-P450 cells. The activity levels of P450s in Ad-P450 cells and human hepatocytes were calculated via simultaneous liquid chromatography/tandem mass spectrometry analysis utilizing a P450 substrate cocktail.
We established Ad-P450 cells mimicking the activity levels of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human hepatocytes. We determined the Km values of P450 substrates and IC values of P450 inhibitors in Ad-P450 cells. These values were approximately equivalent to those obtained in previous studies. We investigated the inhibitory effects of 172 health foods that were recently in circulation in Japan on P450-mediated metabolism using Ad-P450 cells. Of the 172 health foods, five products (two products having dietary effects, one turmeric-based product, one collagen-based product, and one propolis-containing product) simultaneously inhibited the five P450s by more than 50%. Another 29 products were also confirmed to inhibit one or more P450s.
We established a comprehensive assessment system to elucidate the effects of health foods on P450-mediated metabolism and identified the inhibitory activity of 34 of 172 health foods toward the drug-metabolizing P450s. Our results may provide useful information to predict health food-drug interactions.
保健食品在日本已广泛销售和消费。随着保健食品市场的不断扩大，与之相关的不良反应报告有所增加。虽然从保健食品安全有效使用的角度来看，保健食品与药物的相互作用是一个特别令人关注的问题，但由于缺乏评估保健食品对药物代谢影响的既定方法，关于此类相互作用的信息有限。因此，我们开发了模拟细胞色素P450 1A2（CYP1A2）、CYP2C9、CYP2C19、CYP2D6和CYP3A4活性的细胞，这些细胞在人肝细胞的药物代谢中起重要作用，并建立了一个评估保健食品对P450介导的代谢抑制活性的系统。
我们用五种表达P450的腺病毒（Ad-CYP1A2、Ad-CYP2C9、Ad-CYP2C19、Ad-CYP2D6和Ad-CYP3A4）同时感染HepG2细胞，以模拟这些P450在人肝细胞中的活性水平，并将其命名为Ad-P450细胞。通过使用P450底物混合物的同时液相色谱/串联质谱分析来计算Ad-P450细胞和人肝细胞中P450的活性水平。
我们建立了模拟人肝细胞中CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4活性水平的Ad-P450细胞。我们测定了Ad-P450细胞中P450底物的Km值和P450抑制剂的IC值。这些值与先前研究中获得的值大致相当。我们使用Ad-P450细胞研究了日本近期流通的172种保健食品对P450介导的代谢的抑制作用。在这172种保健食品中，有五种产品（两种具有饮食作用的产品、一种姜黄基产品、一种胶原蛋白基产品和一种含蜂胶产品）同时对五种P450的抑制率超过50%。另外29种产品也被证实抑制一种或多种P450。
我们建立了一个全面的评估系统，以阐明保健食品对P450介导的代谢的影响，并确定了172种保健食品中的34种对药物代谢P450的抑制活性。我们的结果可能为预测保健食品与药物的相互作用提供有用信息。
