Haque A K M Mahmudul, Leong Kok Hoong, Lo Yoke Lin, Awang Khalijah, Nagoor Noor Hasima
Institute of Biological Sciences (Genetics and Molecular Biology), Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia.
Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia; Centre of Natural Products and Drug Discovery (CENAR), University of Malaya, 50603 Kuala Lumpur, Malaysia.
Phytomedicine. 2017 Jul 15;31:1-9. doi: 10.1016/j.phymed.2017.05.002. Epub 2017 May 3.
The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain.
The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity. Thus, evaluating the inhibitory potential of a new chemical entity, and to clarify the mechanism of inhibition and kinetics in the various CYP enzymes is an important step to predict drug-drug interactions.
This study was designed to assess the potential inhibitory effects of Alpinia conchigera Griff. rhizomes extract and its active constituent, ACA, on nine c-DNA expressed human cytochrome P450s (CYPs) enzymes using fluorescent CYP inhibition assay.
METHODS/RESULTS: The half maximal inhibitory concentration (IC) of Alpinia conchigera Griff. rhizomes extract and ACA was determined for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A. conchigera extract only moderately inhibits on CYP3A4 (IC = 6.76 ± 1.88µg/ml) whereas ACA moderately inhibits the activities of CYP1A2 (IC = 4.50 ± 0.10µM), CYP2D6 (IC = 7.50 ± 0.17µM) and CYP3A4 (IC = 9.50 ± 0.57µM) while other isoenzymes are weakly inhibited. In addition, mechanism-based inhibition studies reveal that CYP1A2 and CYP3A4 exhibited non-mechanism based inhibition whereas CYP2D6 showed mechanism-based inhibition. Lineweaver-Burk plots depict that ACA competitively inhibited both CYP1A2 and CYP3A4, with a K values of 2.36 ± 0.03 µM and 5.55 ± 0.06µM, respectively, and mixed inhibition towards CYP2D6 with a K value of 4.50 ± 0.08µM. Further, molecular docking studies show that ACA is bound to a few key amino acid residues in the active sites of CYP1A2 and CYP3A4, while one amino residue of CYP2D6 through predominantly Pi-Pi interactions.
Overall, ACA may demonstrate drug-drug interactions when co-administered with other therapeutic drugs that are metabolized by CYP1A2, CYP2D6 or CYP3A4 enzymes. Further in vivo studies, however, are needed to evaluate the clinical significance of these interactions.
从马来西亚民族药用植物山姜（Alpinia conchigera Griff.，姜科）的根茎中分离出的化合物1'-S-1'-乙酰氧基查维酮乙酸酯（ACA），先前已显示出具有体内抗肿瘤活性。在开发新的药物实体时，需要确定该化合物与细胞色素P450超家族代谢酶的潜在相互作用。
同时使用治疗药物可能会通过降低或增加所给药药物的血浆水平而导致潜在的药物-药物相互作用，从而导致临床疗效欠佳或毒性风险更高。因此，评估新化学实体的抑制潜力，并阐明其在各种CYP酶中的抑制机制和动力学，是预测药物-药物相互作用的重要步骤。
本研究旨在使用荧光CYP抑制试验评估山姜根茎提取物及其活性成分ACA对9种c-DNA表达的人细胞色素P450（CYPs）酶的潜在抑制作用。
方法/结果：测定了山姜根茎提取物和ACA对CYP1A2、CYP2A6、CYP2B6、CYP2C8、CYP2C19、CYP2D6、CYP2E1、CYP3A4和CYP3A5的半数最大抑制浓度（IC）。山姜提取物仅对CYP3A4有中度抑制作用（IC = 6.76±1.88μg/ml），而ACA对CYP1A2（IC = 4.50±0.10μM）、CYP2D6（IC = 7.50±0.17μM）和CYP3A4（IC = 9.50±0.57μM）的活性有中度抑制作用，而对其他同工酶的抑制作用较弱。此外基于机制的抑制研究表明，CYP1A2和CYP3A4表现出非基于机制的抑制作用，而CYP2D6表现出基于机制的抑制作用。Lineweaver-Burk图表明，ACA对CYP1A2和CYP3A4均有竞争性抑制作用，其K值分别为2.36±0.03μM和5.55±0.06μM，对CYP2D6有混合抑制作用，K值为4.50±0.08μM。此外，分子对接研究表明，ACA与CYP1A2和CYP3A4活性位点中的一些关键氨基酸残基结合，而与CYP2D6的一个氨基酸残基主要通过π-π相互作用结合。
总体而言，当ACA与其他由CYP1A2、CYP2D6或CYP3A4酶代谢的治疗药物合用时，可能会表现出药物-药物相互作用。然而，需要进一步的体内研究来评估这些相互作用的临床意义。
