中药附子的毒性给临床带来风险。其毒效成分是双酯型乌头类生物碱（DDAs），安全窗窄。故附子个体化用药是临床安全使用之关键，但尚未研究。我们发现DDAs易被CYP3A4/5代谢和被外排转运蛋白（ETs）外排，使其生物利用度并不高（<7%）；又发现DDAs可干预核受体（NRs）而诱导ETs过表达而反制约其过度入血。由此，认为NRs介导的CYP3A/ETs与DDAs的反作用是DDAs适度入血的关键。CYP3A/ETs/NRs三元素的基因多态性和DDAs对它们基因的反调节，是附子个体化用药的重要机制。故课题采用基因多样性的多杂交系DO小鼠和细胞模型，运用基因组学等方法研究三元素基因多态性对DDAs入血的影响，并探讨DDAs对三元素基因表达的作用。以期为附子个体化用药提供依据，亦为后续开展附子临床个体化治疗提供实验基础。

Fuzi, the lateral roots of Aconitum Carmichaeli Debx, is a frequently used traditional Chinese medicine for more than two thousands of years. The major active/toxic components in Fuzi are aconitum alkaloids, mainly including diester-diterpene alkaloids (DDAs), monoester-diterpene alkaloids (MDAs) and aconines. It was reported that DDAs have the strongest effectivenesses in treating diseases such as rheumatics and inflammation. But DDAs also have the highest toxicity in the heart and nervous system with a very narrow safty window, which limits the safe usage of Fuzi in clinical therapeutics. Therefore, for greater effectiveness and minor toxicity, reasonably controlling the exposed concentration of DDAs in vivo it is very important for Fuzi clinical practices. However, individual differences lead to diversely absorption and elimination of DDAs. Therefore, the personalized practice of Fuzi, would be a necessary novel strategy for obtaining the less toxicity and greater effectiveness of Fuzi. .Our previous study showed that aconitine has an extremely low bioavailability (<7%), implying that the toxicity of Fuzi is ascribed to itself. We have revealed that coupling of CYP3A4/5 and efflux transporters (ETs), two key elements for the first line defense of the body in eliminating xenobiotics, controlled the exposed behavior of DDAs in vivo. DDAs were metabolized by CYP3A4/5 for their detoxicification, and excreted by ETs for their elimination. Moreover, we also found that DDAs up-regulated the gene and protein expressions of P-gp via transactivating PXR nuclear receptor (NR). Taken together, we have demonstrated that the bio-directional effects between DDAs and CYP3A/ETs/NRs could harmonize the blood concentration of DDAs in vivo. Therefore, our hypothesis in the proposal is that CYP3A/ETs/NRs would be major and important key elements for the personalized Fuzi practice because the diverse polymorphism of CYP3A/ETs/NRs could regulate the personal different exposure of DDAs in vivo. .Accordingly, in our proposed study, the diversity outbred (DO) mice that are cross-bred from 8 different mouse stains, and transfected cells will be employed for investigating the personalized characteristics of Fuzi in its toxicity and effectiveness. And gene polymorphism, genomic and epigenetic variations of CYP3A, ETs and NRs will be analyzed by personal genome machine. On the other hand, the mechanism of DDAs in regulating the transcriptional activations of CYP3A and ETs by NRs pathway will also be investigated using the cultured cell models. In conclusion, the newly generated findings from our proposed studies would shed light on the experimental principle for the personalized Fuzi clinical practice.