模式生物斑马鱼对7-羟基黄酮代谢的合理性研究

Reasonability of 7-hydroxyflavone metabolism in zebrafish

目的:采用模式生物斑马鱼研究7-羟基黄酮化合物的代谢,探索斑马鱼用于早期、快速预测药物代谢的可行性及合理性。方法:将斑马鱼暴露于7-羟基黄酮化合物溶液中24 h,采用高效液相色谱-电喷雾质谱联用检测斑马鱼体及鱼体外药液,根据准分子离子峰获得化合物相对分子质量信息。通过与文献数据或对照品对照,结合碎片离子,推导可能的代谢产物。结果:正、负离子模式下在斑马鱼体内或体外药液检测到7-羟基黄酮原形及其1个单羟基葡萄糖醛酸结合物和1个单羟基硫酸结合物。结论:斑马鱼对7-羟基黄酮的代谢与7-羟基黄酮已有体内外的II相代谢机制一致,提示斑马鱼模拟现有药物II相代谢具合理性,更具有化合物用量少,成本低、简单高效的优势,是一种在新药早期发现过程中快速预测化合物在体代谢的模式生物新模型。

Objective ： To use the model organism zebrafish in metabolism study of 7-hydroxyflavone for the first time, and to investigate reasonability of applying zebrafish in quick prediction on metabolism in early stage of drug development. Methods ： Zebrafish was exposed to 7-hydroxyflavone solution for 24 h, and the samples of solution and zebrafish body were analyzed by a high performance liquid chromatography-electrospray mass spectrometry （HPLC-ESI-MS） method. The quasi-molecular ions of compounds in both negative and positive mode were observed for molecule mass information, and the potential structures were identified by attentive studying on the mass spectra of compounds and comparing with reference data or standards and ion fragments. Results： In addition to parent compound, 2 phase Ⅱ metabolites were identified, including one glucuronidation product and one sulfation product. Conclusion： Metabolism of 7-hydroxyflavone in zebrafish is consistent with that from studies by current regular in vivo and in vitro methods, indicating that it is reasonable for zebrafish to imitate current phase Ⅱ metabolism. Zebrafish model has advantages of lower cost, far less amount compound, which may become a novel organism model for quick predication on metabolism of new drug development simpler and higher efficiency, even mircoamount compound in new drug development.