氢溴酸槟榔碱对人肝CYP450 酶的体外影响

Effect of arecoline hydrobromide on human hepatic cytochrome P450 activity in vitro

摘要:

目的 采用液质联用法结合特异性探针技术，研究氢溴酸槟榔碱（AH）对人肝微粒体（HLM） 中细胞色素P450（CYP450）亚型酶的体外影响。方法 将CYP1A2、2E1、3A4、2C9、2D6、2B6 的探针 底物分别在0 ～ 160μmol/L AH 的HLM 中温孵，高效液相法测定CYP1A2、2E1、3A4、2C9 的酶活性；高 效液相色谱- 串联质谱仪测定CYP2D6、2B6 的酶活性。结果 AH 对HLM 中CYP2D6、2B6、2E1、2C9 的酶活性有轻微抑制作用，且随AH 浓度的升高而增强。当AH 为160μmol/L 时，对CYP2D6、2B6、2E1、 2C9 酶活性的抑制率分别为36.2%、38.3%、35.0% 和35.4%。结论 槟榔嗜好者使用CYP1A2、2E1、3A4、 2C9、2D6、2B6 6 个CYP450 酶的底物药物时，其代谢相互作用的风险仍不可忽视。

Abstract:

Objective To observe the influences of arecoline hydrobromide (AH) on human hepatic cytochrome P450 activity in vitro by high performance liquid chromatography-mass spectrometry (HPLC-MS) and a cocktail probe substrates method. Methods In this study, six probe substrates of CYP1A2, 2E1, 3A4, 2C9, 2D6 and 2B6 were simultaneously incubated with human liver microsome (HLM) and AH (0-160 μmol/L). The activity of CYP1A2, 2E1, 3A4 and 2C9 was determined by HPLC, and the activity of CYP2D6 and 2B6 was determined by HPLC-MS. Results The activity of CYP2D6, 2B6, 2E1 and 2C9 in HLM was slightly inhibited by AH, which was concentration-dependent. When the AH concentration was 160 μmol/L, the inhibitory rates of the activity of CYP2D6, 2B6, 2E1 and 2C9 in HLM were 36.2%, 38.3%, 35.0% and 35.4%, respectively. Conclusions The risk of metabolic interaction should not be neglected when the substrate drugs of the six kinds of cytochrome P450 isoforms are administered in betelnut addicts.