The Effects Of Scoparone On CYPs And MDR1 Through Activation Of CAR In Vitro

Background: Scoparone(SCO, C₁₁H₁₀O₄), is the main effective monomer of Yin chen or Yinchenhao, which is the most important component of Yinchenhao soup and Yinzhihuang. Scoparone has many pharmacological properties such as heat and toxic substance clearance, anti-inflammation, choleretic, hepato-protetive, anti-thrombus and anti-allergic. It is widely used to treat jaundice, hepatitis, cirrhosis, hepatoma, bronchial asthma and thrombus in clinic at present. Research has found the mechanism for yin zhi huang to lower bilirubin, which is principally through CAR to induce the main transporter such as MRP2, UGT, GST and so on. At the same time, they screened the ligands of CAR existing in Yinzhihuang, and found one effective monomer is Scoparone.On the other hand, more and more research have found that CAR or PXR could active the transcription level of CYP2C9, CYP2C19, CYP3A4 and MDR1, among which CYP2C9, CYP2C19 and CYP3A4 are responsible for metabolism of more than 60 percent clinically used drugs. P-glycoprotein, coded by multidrug resistence gene (MDR1; ABCB 1) and widely located at human normal tissues such as liver, kidney, small intestine and brain, plays the key role in drug absorption, distribution and elimination. Also, P-glycoprotein inhibitors are very important for reversement of multiple resistences of antitumor drugs.To sum up, scoparone can induce CAR, and CAR can active the transcription level of CYP2C9, CYP2C19, CYP3A4 and MDR1, and then, whether scoparone could induce these enzymes and deug transporter? If can, is the mechanism through activiton of CAR?Aims: To find whether scoparone could induce CYP2C9, CYP2C19, CYP3A4 and MDR1 in vitro; If could, we will find whether the induction of scoparone to CYP2C9, CYP2C19, CYP3A4 and MDR1 is through CAR.Method: By setting up cell-based high-through platform in vitro, the effects of scoparone on transcription of several important CYP450 enzymes and MDR1 have been explored at mRNA level and by dual-luciferase activity detection, whether these effects are through acitivation of CAR have been studied.Results: 1. scoparone (20μM) could significantly maximally induce CYP2C9, CYP2C19, CYP3A4 and MDR1 at mRNA level; 2. scoparone (20μM) could significantly maximally increase the dual-luciferase eporter activities of CYP2C9, CYP2C19, CYP3A4 and MDR1 through CAR.Conclusion: The present study has found that scoparone could increase the expression of CYP2C9, CYP2C19, CYP3A4 and MDR1 through CAR in molecular and cellor mechanism, and proved scoparone is the potential utilitychemistry noumenon for drug discovery and treatments of liver diseases. Attention should be paid for clinicians to avoid related drug interactions when scoparone is used with CYP2C9, CYP2C19, CYP3A4 and MDR1 substrate drugs. And further studies in clinic are needed to confirm above conclusioins.