Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, PR China; Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, PR China.
Department of Molecular Biology and Human Genetics, Tzu Chi University. No 701 Sec 3 Chun Yang Rd. Hualian City, Taiwan.
J Ethnopharmacol. 2015 Jun 20;168:146-9. doi: 10.1016/j.jep.2015.03.061. Epub 2015 Apr 7.
Alantolactone (AL), one of the main active ingredients in Inula helenium L., has been included in various prescriptions of traditional Chinese medicine. The effects of AL on cytochrome P450 (CYP450) were still unclear. This study evaluated the inhibitory effect of AL on cytochrome P450s in vitro and in vivo.
The inhibitory effects of AL on the CYPs activity were evaluated in human liver microsomes (HLMs) and recombinant cDNA-expressed enzymes incubation system, and then determined by LC-MS/MS based CYPs probe substrate assay. C57BL/6 mice were treated AL orally (0, 25, 50, 100 mg/kg) for 15 days. The inhibitory effects of AL on major Cyps in mice were examined at both the mRNA and enzyme activity levels.
AL showed a potent inhibitory effect on CYP3A4 activity with IC50 values of 3.599 (HLMs) and 3.90 (recombinant CYP3A4) μM, respectively. AL strongly decreased CYP3A4 activity in a dose-dependent but not time-dependent way in HLMs. Results from typical Lineweaver-Burk plots showed that AL could inhibit CYP3A4 activity noncompetitively, with a Ki value of 1.09 μM in HLMs. Moreover, activity of CYP2C19 could also be inhibited by AL with IC50 of 36.82 μM. Other CYP450 isoforms were not markedly affected by AL. The inhibition was also validated by in vivo study of mice. AL significantly decreased mRNA expression of Cyp2c and 3a family.
The study indicates that herb-drug interaction should be paid more attention between AL and drugs metabolized by CYP3A4.
土木香内酯（AL）是土木香中的主要活性成分之一，已被纳入多种中药处方。AL 对细胞色素 P450（CYP450）的影响尚不清楚。本研究评估了 AL 对体外和体内细胞色素 P450 的抑制作用。
在人肝微粒体（HLMs）和重组 cDNA 表达酶孵育系统中评估 AL 对 CYP 酶活性的抑制作用，并通过基于 LC-MS/MS 的 CYP 探针底物测定法进行测定。C57BL/6 小鼠经口给予 AL（0、25、50、100mg/kg）15 天。在 mRNA 和酶活性水平上检测 AL 对小鼠主要 Cyps 的抑制作用。
AL 对 CYP3A4 活性表现出很强的抑制作用，IC50 值分别为 3.599（HLMs）和 3.90（重组 CYP3A4）μM。AL 在 HLMs 中以剂量依赖性而非时间依赖性方式强烈降低 CYP3A4 活性。典型的 Lineweaver-Burk 图结果表明，AL 可以非竞争性地抑制 CYP3A4 活性，在 HLMs 中的 Ki 值为 1.09μM。此外，AL 还可以抑制 CYP2C19 的活性，IC50 为 36.82μM。其他 CYP450 同工酶不受 AL 的显著影响。体内研究也验证了这种抑制作用。AL 显著降低 Cyp2c 和 3a 家族的 mRNA 表达。
研究表明，在 AL 和由 CYP3A4 代谢的药物之间，应该更加注意草药-药物相互作用。
