Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Phytother Res. 2015 Jun;29(6):825-34. doi: 10.1002/ptr.5285. Epub 2015 Jan 30.
The three purified herbal compounds tetrahydropalmatine (Tet), neferine and berberine (Ber) were explored in vitro for basic inhibition mechanisms towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Phenacetin, dextromethorphan and testosterone, respectively, were used as CYP1A2, CYP2D6 and CYP3A4 substrates, and their metabolites were determined by validated HPLC methodologies. Positive inhibition controls were used. Mechanism-based (irreversible) inhibition was assessed by time-dependent and nicotinamide adenine dinucleotide phosphate-dependent and reversible inhibition by Lineweaver-Burk plot assessments. Inhibition mechanisms were also assessed by computerized interaction prediction by using the Discovery Studio CDOCKER software (Accelrys, San Diego, CA, USA). Tetrahydropalmatine showed a mechanism-based inhibition of both CYP1A2 and CYP2D6, and Ber of CYP2D6. Neferine and Ber both showed a nonmechanistic inhibition of CYP1A2. All compounds showed a similar and significant mechanism-based inhibition of CYP3A4. Tetrahydropalmatine and Ber demonstrated both reversible and irreversible inhibition of CYP2D6 and CYP3A4. Tetrahydropalmatine and Ber displayed H-bond and several Pi-bond connections with specific amino acid residues of CYP1A2, CYP2D6 and CYP3A4, giving further knowledge to the identified reversible and irreversible herb-drug interactions. Tetrahydropalmatine and Ber should be considered for herb-drug interactions in clinical therapy until relevant clinical studies are available.
三种纯化的草药化合物延胡索乙素（Tet）、小檗碱和黄连素（Ber）被探索用于体外对重组人 CYP1A2、CYP2D6 和 CYP3A4 代谢活性的基本抑制机制。分别使用非那西汀、右美沙芬和睾酮作为 CYP1A2、CYP2D6 和 CYP3A4 的底物，并用验证的 HPLC 方法测定其代谢物。使用阳性抑制对照。通过时间依赖性和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）依赖性以及 Lineweaver-Burk 图评估的可逆抑制来评估基于机制的（不可逆）抑制。还通过使用 Discovery Studio CDOCKER 软件（Accelrys，圣地亚哥，CA，USA）进行计算机化相互作用预测来评估抑制机制。延胡索乙素显示对 CYP1A2 和 CYP2D6 以及黄连素对 CYP2D6 的基于机制的抑制作用。小檗碱和黄连素均显示对 CYP1A2 的非机制抑制作用。所有化合物均显示对 CYP3A4 的类似且显著的基于机制的抑制作用。延胡索乙素和黄连素对 CYP2D6 和 CYP3A4 显示出可逆和不可逆抑制作用。延胡索乙素和黄连素与 CYP1A2、CYP2D6 和 CYP3A4 的特定氨基酸残基显示出氢键和多个 Pi 键连接，为已确定的可逆和不可逆草药-药物相互作用提供了进一步的知识。在相关临床研究可用之前，应考虑延胡索乙素和黄连素在临床治疗中的草药-药物相互作用。
