CYP3A在人类胆汁酸宿主-肠道微生物协同代谢中的生物学功能研究及其药物代谢组学转化探究

内源性代谢通路和外源性药物代谢途径的相似性或重叠性，即是药物代谢组学实现个体化用药的重要理论基础，也是药物代谢领域的基本科学问题。本项目根据宿主-肠道微生物协同代谢中肠道细菌合成代谢物的“外源性”特性，在申请人团队已发现CYP3A4/3A7专属性催化去氧胆酸氧化为三级胆汁酸的代谢通路基础上，针对CYP3A生物学功能的科学问题，提出了“CYP3A是宿主代谢处置肠道菌群合成次级胆汁酸的特异性机制”的假说。由此，本项目拟系统开展CYP3A在人类胆汁酸宿主-肠道微生物协同代谢中生物学功能相关的胆汁酸组学研究和体外代谢研究，阐明人类主要次级胆汁酸经CYP3A氧化代谢为三级胆汁酸及随后的硫酸化与葡萄糖醛酸化结合代谢位点、专属性和动力学特征；然后选择与次级胆汁酸代谢通路高度重叠的典型探针药物进行CYP3A药物代谢组学的概念验证性探究，以期发展出表征CYP3A功能的原创性胆汁酸生物标志物和模型。

A pivotal biochemical basis for pharmaco-metabolomics is founded on the shared pathways of endogenous and exogenous metabolism. Underlying the shared pathways, there exists a long-standing fundamental question in drug metabolism: “the xenobiotics metabolizing system is part of intermediary metabolism or is a separate system for detoxifying foreign compounds?”. Current ear of systems biology and metagenomics have provided a new vision to reconsider functional biology of drug metabolism in host-gut microbial metabolic interactions. Gut microbiota colonizes and develops after birth, developing important host-gut microbial co-metabolism that is closely associated health and diseases. Interestingly, the bacteria-synthesized small molecule metabolites are “endogenous” to the host-gut microbial symbiote, however, are definitely “exogenous” to the host genome. It is therefore proposed that human genome has evolved a specific system in response to the “exogenous” metabolites synthesized by gut microbiota, and the specific system might be what we know as drug metabolism. Based on the hypothesis, this work focuses on functional biology of CYP3A in detoxifying gut bacteria-synthesized secondary C24 bile acids (BAs). Following our recently identified CYP3A4/3A7-catalyzed tertiary stereoselective oxidation pathways of deoxycholate species, this project aims to systematically investigate the functional roles of CYP3A in disposing primary, secondary and tertiary BAs in human. The characterized specific reactions will be preliminarily tested in transitional pharmaco-metabolomic studies to validate their marker efficacies to predict the exposure and clearance of probe drugs disposed in similar pathways. This project will substantially improve our understanding of the inherent functional biological roles of CYP3A, the most important members of drug metabolizing enzymes. New findings obtained in this study will creatively help the development of novel functional biomarkers of CYP3A activities in the ear of precise medicine.