新兴消毒副产物卤代苯醌的体外胃肠道、肝代谢模拟及相关毒性研究

卤代苯醌(HBQs)因其毒性远高于常规消毒副产物而备受关注。目前基于细胞的体外毒性研究因缺乏胃肠道、肝代谢等体内过程而不能反映HBQs对人的实际影响；而体内动物实验也因研究少、种属差异大等情况很难为HBQs的健康风险评价提供有效的参考。基于此，本项目拟以饮用水常见HBQs为实验对象，利用体外代谢模型，研究HBQs经人胃肠道（胃液、小肠液、大肠菌液、肠壁）、肝（Ⅰ相、Ⅱ相反应）代谢后结构的转化，鉴定代谢产物，揭示HBQs代谢通路；同时利用人源细胞评价HBQs经过胃肠道、肝代谢后毒性（细胞遗传毒性等，下同）的变化，鉴定重要代谢产物的毒性特征，阐明HBQs在胃肠道、肝代谢过程中的毒作用转化机制；在此基础上，进一步比较人与其它物种HBQs肝代谢动力学、代谢表型、代谢产物及毒性的差异，鉴别出与人肝代谢最接近的物种。本项目将为HBQs的健康风险评价提供基础数据，为将来HBQs体内安全评价实验指明方向。

Halobenzoquinones (HBQs) has received great attention due to its much higher toxicity as compared to the conventional disinfection byproducts. At present, in vitro toxicity studies based on cells are difficult to reflect the actual effects of HBQs on human beings due to the lack of in vivo processes such as gastrointestinal metabolism and liver metabolism. While in vivo (animal) studies also cannot provide an effective reference for the health risk assessment of HBQs due to the limited studies and the great species difference in toxic reaction to HBQs. Based on this, this project aims to study the structure transformation after HBQs (the species widely occurred in drinking water) experiencing gastrointestinal metabolism (gastric fluid, intestinal fluid, gut bacteria and intestinal wall metabolism) and liver metabolism (I phase and II phase reaction) by using in vitro models. The metabolites will be identified and the metabolic pathways will be revealed. At the same time, human cells will be used to evaluate the toxicity (cytotoxicity, genotoxicity and etc, the same below) variation after HBQs experienced gastrointestinal and liver metabolism, and characterize the toxicity of important metabolite, and thus elucidate the mechanism of toxicity transformation during HBQs metabolism in gastrointestinal tract and liver. After that, the liver metabolism of HBQs (including metabolism kinetics, metabolic phenotype, metabolites and toxicity) will be further compared between human and other model animals, trying to identify the species that have similar characteristics with human in HBQs metabolism. This project will provide basic information for the health risk assessment of HBQs and give guidance for future safety assessment experiments of HBQs in vivo.