Jiang Bo, Meng Liyuan, Zhang Feng, Jin Xiaoling, Zhang Guiliang
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Core Facility of Basic Medical Sciences, Basic Medicine Faculty of Shanghai Jiao Tong University, Shanghai 200025, China.
Life Sci. 2017 Nov 15;189:1-7. doi: 10.1016/j.lfs.2017.09.011. Epub 2017 Sep 8.
Berberine (BER) is an important anti-bacterial drug from Chinese herbal medicine and a novel drug candidate for preclinical development in recent years. Here we provide evidence that the effects of berberine on cytochrome P450 (CYP) 1A2 in vitro and in vivo.
Real-time polymerase chain reaction and western blotting analysis were employed to evaluate the CYP1A2 mRNA levels and protein expression. The enzyme activity was assessed by the metabolic rate of phenacetin to acetaminophen by LC-MS/MS method.
The results indicated that the CYP1A2 mRNA expression and enzyme activity in HepG2 cells after treated with BER (4.5μg/ml) exhibited a significant induction (16.11-fold and 5.0-fold, respectively), which was consistent with those on rat liver microsomes (4.5-fold and 1.98-fold, respectively) by BER induction (10mg/kg/day, i.p.) ex vivo. Beside, BER induced CYP1A2 activity with increases in AUC and C of acetaminophen and the Ke and t of phenacetin after oral administration of phenacetin (p<0.05) in vivo.
This study firstly reported the induction effect of BER on rats CYP1A2 by intraperitoneal route. But, BER didn't show significant induction effect on CYP1A2 by high-dose orally administrating to rats for 6 consecutive days due to the extremely low bioavailability. The potential drug-drug interactions were supposed to happen when the liver exposed to high dose of BER in vivo by changing administration route.
黄连素（BER）是一种重要的来自中药的抗菌药物，也是近年来临床前开发的新型候选药物。在此，我们提供证据证明黄连素在体外和体内对细胞色素P450（CYP）1A2的影响。
采用实时聚合酶链反应和蛋白质免疫印迹分析来评估CYP1A2 mRNA水平和蛋白质表达。通过液相色谱 - 串联质谱法测定非那西丁代谢为对乙酰氨基酚的代谢率来评估酶活性。
结果表明，用BER（4.5μg/ml）处理后的HepG2细胞中CYP1A2 mRNA表达和酶活性呈现显著诱导（分别为16.11倍和5.0倍），这与离体用BER诱导（10mg/kg/天，腹腔注射）大鼠肝微粒体中的结果一致（分别为4.5倍和1.98倍）。此外，在体内口服非那西丁后，BER诱导CYP1A2活性，同时对乙酰氨基酚的AUC和C增加，非那西丁的Ke和t增加（p<0.05）。
本研究首次报道了腹腔注射途径下BER对大鼠CYP1A2的诱导作用。但是，由于生物利用度极低，连续6天对大鼠高剂量口服BER对CYP1A2未显示出显著诱导作用。当肝脏在体内暴露于高剂量的BER时，通过改变给药途径可能会发生潜在的药物相互作用。
