<i>In vitro</i> study on the effect of peucedanol on the activity of cytochrome P450 enzymes

Peucedanol is a major extract of <i>Peucedanum japonicum</i> Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. The interaction between peucedanol and CYP450s was investigated. Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 μM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters <i>in vitro</i>. Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC₅₀ values of 6.03, 13.57, and 7.58 μM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a <i>K_i</i> value of 4.07 μM and a competitive inhibitor of CYP1A2 and 2D6 with a <i>K_i</i> values of 3.39 and 6.77 μM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the <i>K_i</i>/<i>K_inact</i> value of 5.44/0.046 min/μM. <i>In vitro</i> inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further <i>in vivo</i> validation.

前胡醇（Peucedanol）是日本前胡（*Peucedanum japonicum* Thunb.，伞形科（Apiaceae））根部的主要提取物，该药材为儿科常用草药。其与细胞色素P450酶（cytochrome P450 enzymes, CYP450s）的相互作用可能引发不良反应，甚至导致治疗失败。本研究围绕前胡醇与CYP450s的相互作用开展探究。将浓度为0、2.5、5、10、25、50及100 μM的前胡醇，与8种人源肝脏CYP亚型（CYP1A2、2A6、3A4、2C8、2C9、2C19、2D6及2E1）在混合人肝微粒体（pooled human liver microsomes, HLMs）中共同孵育30分钟，以特异性抑制剂为阳性对照，未处理的HLMs为阴性对照。通过酶动力学实验与时间梯度为0、5、10、15及30分钟的时间依赖性实验，获取体外（in vitro）相关参数。实验结果显示，前胡醇可剂量依赖性显著抑制CYP1A2、2D6及3A4的活性，其半数抑制浓度（IC50）分别为6.03、13.57与7.58 μM。前胡醇对CYP3A4为非竞争性抑制剂，抑制常数（Ki）为4.07 μM；对CYP1A2与2D6为竞争性抑制剂，Ki值分别为3.39与6.77 μM。此外，前胡醇对CYP3A4的抑制作用呈时间依赖性，其Ki/Kinact值为5.44/0.046 min/μM。本研究报道了前胡醇在体外对CYP1A2、2A6及3A4活性的抑制作用。由于上述CYP亚型参与多种药物的代谢过程，上述结果提示前胡醇与经CYP1A2、2D6及3A4代谢的药物之间存在潜在的药物-药物相互作用，该结论尚需体内（in vivo）实验进一步验证。