Study On The Interaction And Pharmacological Action Of White Peony, Salvia Miltiorrhiza And Veratrum

Eighteen incompatible medicaments is an important theory in Traditional Chinese Medicine (TCM). The theory suggests that drugs in the eighteen incompatible medicaments can be toxic when used together. Radix Paeoniae Alba and Veratrum nigrum L. belong to the eighteen incompatible medicaments. As such, their concurrent use has been prohibited for thousands of years. However, in ancient Chinese medicine few studies have assessed the compatibility of Radix Paeoniae Alba and Veratrum nigrum L. for the treatment of diseases. So it has great significance for the research of eighteen incompatible medicaments.This study offers preliminary insight into the mechanism and chemical constitutents responsible for the incompatibility and toxicity of Radix Paeoniae Alba and Veratrum nigrum L.. Specifically, we performed toxicology studies to identify and quantify the constituent substances of the two agents, and identify how and why they are incompatible. Experiments in mice revealed that LD50 toxic dose of Veratrum nigrum L. was 2.566g/kg, and acute toxicity increases when the dose of Veratrum nigrum L.is higher than, or equal to, Radix Paeoniae Alba, especially at the ratio of 8:1 and 1:1. Ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC-TOF-MS) analysis showed that, although the volumes of Veratrum nigrum L. were the same, the content of some veratrum alkaloids changed significantly, This suggests that the increased toxicity of the Veratrum nigrum L.-Radix Paeoniae Alba combination was due mainly to increased content of the special veratrum alkaloids. Further investigations showed that the cytotoxicity of veratridine in SH-SY5Y cells was decreased with increasing paeoniflorin concentrations. This study provides insight into the mechanism behind the incompatibility theory of TCM, and suggests that further studies into their development and application are needed.Danshen, the dried root of Salvia miltiorrhiza,has been widely used in China and other countries for the treatment of cardiovascular, metabolic diseases, hepatic fibrosis and IBD for a long time, Tanshinone IIA (Tan IIA, C19H18O3) is one of the main natural active ingredients purified from Danshen. Tan IIA has been widely used in clinical practice for its remarkable pharmacological activities. Cytochrome P450 is widely involved in drug metabolism and the physiological pathological process, while the PXR receptor is the important transcription regulator of P450 PXR can activate CYP3A to protect body against the injury and produce mutual interaction between the drugs. According to the latest research: PXR is not only involved in drug metabolism, and it participate in variety of metabolic diseases (such as lipid metabolism, bile acid metabolism) and IBD, PXR can be used as a candidate of therapeutic target for drug screening. So we study the correlation of Tan IIA and PXR to reveal the essential mechanism of the Tan IIA as a mumber of eighteen incompatible medicaments.Study found that Tan IIA has significant PXR-CYP3A4 inductionability. HepG2 cells and LS174T cells were used to investigate the vitrol effects of Tan IIA on PXR and CP3A4. The in vitro study demonstrated that Tan IIA is an efficacious PXR agonist that could induce the expression of PXR and CYP3A4 in a strong dose-and time-dependent manner. The induction effect of Tan IIA on CYP3A4 was mediated by the transactivation of PXR.Gut-formed LCA is hepatotoxic, and has been implicated in the pathogenesis of cholestatic diseases. The research showed that LCA can activate PXR and induce CYP3A expression, and it can reduced the liver injury caused by cholestasis. Thus, the PXR pathway can play an important role in maintain the internal environment homeostasis. To further investigate the hepatoprotective mechanisms of Tan IIA against LCA-induced cholestasis in vivo, we used wild-type and PXR-knockdown mice to explore the effect of Tan IIA on LCA-induced hepatotoxicity, as well as the role of PXR in these effects. We found that Tan IIA could protect against LCA-induced hepatotoxicity and cholestasis, and the hepatoprotective effects of Tan IIA were partially caused by the upregulation of PXR, as well as Cyp3a11, Cyp3a13, and Mdrl a, which are the enzymes responsible for LCA metabolism. This is the first report showing that the hepatoprotective effects of Tan IIA are partly mediated by PXR.Modern studies have demonstrated that PXR activation ameliorated dextran sodium sulfate (DSS)-induced colitis in mice via nuclear factor-kappa B (NF-κB) target gene expression, suggesting PXR as a modulator of intestinal inflammation. And PXR-silenced mice treated with Tan IIA demonstrated low protection against DSS-induced mouse IBD and exacerbated the severity of IBD compared with wild-type mice, PXR silenced mice demonstrated the necessity for PXR in Tan IIA-mediated up-regulation of xenobiotic metabolism genes. The IBD treatment effects of Tan IIA are partially due to PXR-mediated up-regulation of xenobiotic metabolism and down-regulation of inflammatory mediators. The novel findings reported here may contribute to the effective utilization of Tan IIA and its derivatives as a PXR ligand in the treatment of human IBD. This suggests that Tan IIA may have considerable clinical utility.