黄曲霉毒素B1、G1和B2在畜禽中的生物转化规律和种属代谢差异研究

Aflatoxins (AFT) has contaminated extensively in cereals and feeds, which possess high toxicity and strong carcinogenicity. Aflatoxins have posed horrible risks for health of animals and human beings and also led to enormous economic loss. It has been reported that the toxicity of aflatoxins is correlated to the metabolic process. It is of great importance, hence, to conduct the metabolism, fully certifying the toxication and detoxification pathways. Currently, merely the metabolism of AFB1 has been fully investigated, the metabolic information for AFG1 and AFB2, however, is limited and implicit. The aim of present study is to conduct the metabolism in vitro and in vivo for AFB1, AFG1 and AFB2 based on high resolution mass spectrometry, systematically clarifying the metabolic pathways, major metabolites, key enzymes participated in the metabolism as well as metabolic species differences (rats, chickens and swine). The successfully implement of present work would definitely provide fundamental data for mechanism of toxication of AFT and the reason of species endurance as well as the identification of the marker residues, reducing threaten of AFT for livestock industries while offering theoretical basis for risk assessment of mycotoxins.

黄曲霉毒素(Aflatoxin, AFT)具有强毒性和强致癌性，在谷物和饲料中污染普遍，严重威胁着动物和人类的健康。AFT的毒性与其代谢过程密切相关，其主要代谢物和致毒/解毒代谢途径的阐明是开展其残留标志物和致毒机制研究的基础。目前，国内外仅阐明了AFB1的主要代谢物，对许多存在的未知代谢物尚未鉴定，尤其是AFG1和AFB2的代谢研究未见文献报道。本项目以AFB1、AFG1和AFB2为研究对象，采用液相串联高分辨质谱开展其在大鼠、鸡、猪、牛和羊肝微粒体中的代谢研究，在此基础上，系统研究其在大鼠、鸡和猪体内代谢，旨在阐明AFT在不同动物的代谢途径和特点、代谢产物、关键代谢酶以及化合物结构与代谢关系，全面揭示其生物转化规律和种属代谢差异。研究结果将为AFT的毒理作用机制研究、种属耐受差异原因解释以及残留标示物的确定提供基础数据，并为控制和减少AFT对畜禽养殖业危害及其风险评估提供科学理论依据。

采用液相串联高分辨质谱技术开展了4种黄曲霉毒素(AFB1、AFB2、AFG1和AFG2)在大鼠、鸡、猪、牛、羊和人中的体外内代谢研究，阐明了4种毒素的主要代谢产物、代谢途径、关键代谢酶与种属代谢差异。本项目共识别和鉴定出了30余种代谢产物，其中多数为首次报道，羟基化、环氧化、脱氢/加氢、O-脱甲基与谷胱甘肽结合反应是4种毒素的主要代谢途径。CYP3A4、CYP2C19和CYP1A2是肝脏中降解4种毒素的关键代谢酶，尤其是CYP3A4酶起着主导作用。4种毒素在畜禽中存在显著的种属代谢差异，它们在禽类鸡肝脏中毒性增强反应(环氧化与脱氢)最为强烈，这为科学解释禽类为何对黄曲霉毒素较为敏感提供了代谢方面的数据支撑。在主要代谢产物方面，黄曲霉毒素的代谢亦存在显著种属代谢差异，AFM1与AFQ1分别是畜禽和人肝脏中优势代谢产物，因此，两者可以分别作为AFB1在畜禽和人中的生物标志物。本项目的研究结果为科学评估黄曲霉毒素对畜禽养殖业的危害提供了数据支撑。