Dipartimento di Scienze del Farmaco, Università "G. D'Annunzio", Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo, Italy.
Phytomedicine. 2011 May 15;18(7):586-91. doi: 10.1016/j.phymed.2010.10.017. Epub 2010 Nov 26.
Previous studies demonstrated that natural prenyloxyphenylpropanoid derivatives have potent biological properties like anti-cancer effects in vitro and in vivo. Additionally they are extremely safe and associated with low toxicity, making them excellent candidates as chemopreventive agents. However, so far only little is known about possible interactions with isoforms of cytochrome P450 (CYPs) being involved in the metabolism of xenobiotics and representing a major site for drug-drug interactions. The aim of this study was to evaluate the effects of selected natural prenyloxyphenylpropanoids (prenyloxycinnamic acids) on expression and activity of some major CYPs and on the activity of the major drug efflux transporter P-glycoprotein (P-gp). Inhibition of CYP3A4, CYP2C19, and CYP2D6 was quantified using commercially available kits. P-gp inhibtion was quantified by calcein assay. Induction of CYP mRNA (CYP3A4, CYP2C19, CYP2C9, and CYP2B6) was measured in LS180 cells by quantitative real-time reverse transcriptase polymerase chain reaction using the LightCycler technology. Only boropinic acid revealed substantial inhibition of CYPs, especially of CYP2C19 (IC₅₀ = 31±5μM). This compound also had the most pronounced effect on CYP mRNA expression among the prenyloxycinnamic acids tested. However all but 4'-isopentenyloxy-p-coumaric acid revealed inducing effects on CYPs with different induction profiles. P-gp was only significantly inhibited by 4'-geranyloxyferulic acid. This was the first study demonstrating modulating effects of prenyloxycinnamic acids on CYP activity and expression and on P-gp activity. The results suggest that boropinic acid is most prone to drug-drug interactions at the level of CYPs, whereas 4'-isopentenyloxy-p-coumaric acid does not modulate CYP activity and expression.
先前的研究表明，天然 prenyl 氧代苯丙烷衍生物具有强大的生物学特性，如体外和体内的抗癌作用。此外，它们非常安全，毒性低，是化学预防剂的理想选择。然而，到目前为止，人们对它们与细胞色素 P450（CYPs）同工型的可能相互作用知之甚少，这些同工型参与了外源性物质的代谢，是药物相互作用的主要部位。本研究旨在评估选定的天然 prenyl 氧代苯丙烷（prenyl 氧代肉桂酸）对一些主要 CYP 的表达和活性以及主要药物外排转运蛋白 P-糖蛋白（P-gp）活性的影响。使用市售试剂盒定量测定 CYP3A4、CYP2C19 和 CYP2D6 的抑制作用。通过钙黄绿素测定法定量测定 P-gp 抑制作用。通过实时定量逆转录聚合酶链反应（LightCycler 技术）测量 LS180 细胞中 CYP mRNA（CYP3A4、CYP2C19、CYP2C9 和 CYP2B6）的诱导。只有硼代酸显示出对 CYP 的实质性抑制作用，特别是对 CYP2C19（IC₅₀=31±5μM）。在测试的 prenyl 氧代肉桂酸中，该化合物对 CYP mRNA 表达的影响也最为显著。然而，除了 4'-异戊烯氧基对香豆酸外，所有化合物都对 CYP 表现出不同的诱导作用。只有 4'-香叶基阿魏酸显著抑制 P-gp。这是第一项证明 prenyl 氧代肉桂酸对 CYP 活性和表达以及 P-gp 活性具有调节作用的研究。结果表明，硼代酸在 CYP 水平上最容易发生药物相互作用，而 4'-异戊烯氧基对香豆酸则不调节 CYP 活性和表达。
