羧酸酯酶是肝脏中表达的药物代谢酶之一，对许多含有酯键的药物代谢具有重要作用，因此，明确影响羧酸酯酶的因素及相关机制对于指导临床合理用药具有重要意义。但目前羧酸酯酶此方面的研究非常有限。本实验室长期致力于代谢酶的研究，发现藤黄酸、LPS和雌激素等因素能够负性调节羧酸酯酶，且MAPK通路的激活在其中起到重要作用，但具体机制不明晰。通过本项目的研究明确羧酸酯酶负性调节的因素及对作为其底物的临床用药的药效的影响，与此同时，明晰MAPK通路的激活与羧酸酯酶负性调节之间的关系，代谢性核受体PXR和CAR在其中的作用，以及MAPK通路的激活与PXR和CAR的磷酸化之间的关系，阐明羧酸酯酶负性调节的确切机制。并以此为基础，明确通过该通路负性调节羧酸酯酶的其它因素；将通路研究结果扩展到其它代谢酶的通路调控中。本项目不仅丰富了代谢酶的研究内容，更为联合用药、炎症患者及孕妇的临床合理用药提供重要的理论依据。

Carboxylesterase, one of the liver drug metabolizing enzymes, plays a key role in drug metabolism of many drugs containing ester bond, therefore, to make clear the factors those will influence carboxylesterase and related mechanisms has important significance in guiding the clinical rational use of drugs. However, at present, the research on this aspect of carboxylesterase is very limited. The laboratory long-term commitment to study metabolic enzyme, found that LPS, gambogic acid and estrogen can negatively regulate carboxylesterase and activation of the MAPK pathway plays an important role in it, but mechanism is not clear. Through this project we can make clearly the factors which down-regulate the expression of carboxylesterase and the effects on the drug which is substrate of carboxylesterase. Meanwhile, clear relationship between carboxylesterase negative regulation and activation of MAPK pathway, role of metabolic nuclear receptors PXR and CAR, and relationship between MAPK pathway activation and phosphorylation of PXR and CAR, clarify the exact mechanism of carboxylesterase down-regulation. Moreover, we can find more factors which negatively regulate carboxylesterase through the same pathway, and the researches of the pathway are extended to the regulation of other metabolic enzymes. This project not only enriches the research content of metabolic enzymes, but also provides an important theoretical basis for the clinical rational use of drugs in the combination of drugs, inflammation and pregnant women.