基于肝微粒体的T-2毒素体外代谢研究
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摘要
作为单端孢霉烯族类真菌毒素的重要代表，T-2毒素在目前已知的该类毒素中毒性最强，因其高毒性，T-2毒素被视为潜在的化学毒剂之一；另外，其亦是自然界存在的最危险的食品污染源之一，近年来对粮农作物造成了广泛污染，对人类的身体健康、食品安全等方面产生了巨大威胁。因此，T-2毒素的相关研究是近年来的研究热点之一。T-2毒素在体内代谢速率较快，其体内持续毒性主要由代谢产物的毒性引起。因此，为深入阐明其毒性，对T-2毒素的代谢研究尤为重要。
以替代(replacement)、减少(reduction)和优化(refinement)动物试验为核心的“3R”运动逐渐被国际社会广泛接受。肝脏是药物毒物最重要的代谢器官，是生物转化的主要场所。以肝脏为基础的体外替代实验，如肝微粒体和肝细胞，在“3R”运动中起着重要的作用，其以特有的优势和特点在外源性物质代谢和毒性的研究中得到广泛应用。
本论文即旨在研究基于肝微粒体的T-2毒素的体外代谢，包括T-2毒素在肝微粒体中代谢的种属差异性，特别是T-2毒素在人肝微粒体中的代谢行为及和动物之间的代谢差异性，研究不同酶系对T-2毒素的代谢作用，期望为T-2毒素代谢机理、代谢与毒性的关系以及与人类健康的风险评估、食品安全研究等提供实验资料和科学依据。
本论文共分为六章，第一章为文献综述，引述文献70余篇，主要论述了近年来T-2毒素在分析方法、体内外代谢等方面的研究进展。
第二章为T-2毒素的两种代谢物即HT-2毒素、3’-OH T-2毒素的参考品制备部分。在分离纯化基础上，对之进行了结构表征；
采用玉米酯酶对T-2毒素进行特异性转化，制备HT-2毒素，产率高达80%以上，该酶催化方法具有定向催化、条件温和及产率高等特点；采用体外肝S9体系生物转化的方法，将T-2毒素定向转化为3’-OH T-2毒素，产率达30%以上。为后续的研究提供了物质基础；
在此基础上，第三章建立了基于液相色谱-质谱技术的T-2毒素及其主要代谢物的同时定量分析检测方法。包括T-2毒素及3’-OH T-2毒素在苯巴比妥诱导的大鼠肝S9中的定量检测方法，及T-2毒素及其五种代谢物在肝微粒体和全血中的分析检测方法。所建方法简单快速，灵敏度高，其回收率、精密度和准确度均符合生物样品定量分析的要求，展示了其用做体内外代谢动力学的良好应用前景；
第四章的体外代谢研究表明，T-2毒素的肝微粒体代谢存在种属差异性，肝固有清除率依次为人＞小鼠＞猴＞比格犬＞大鼠，然而肝清除率的顺序为小鼠＞猴＞大鼠＞比格犬＞人；不同种属肝微粒体对T-2毒素的亲和力和代谢能力存在差异。
第五章为T-2毒素在不同酶体系的体外代谢研究。在人肝微粒体中，多种细胞色素P450（CYP）同工酶参与了T-2毒素的代谢，包括CYP3A4、CYP2E1、CYP1A2、CYP2C9、CYP2B6、CYP2D6、CYP2C19，其中CYP3A4为主要的代谢同工酶，主要以羟基化产物为主；肝微粒体中酯酶对T-2毒素代谢作用明显，主要产物为HT-2毒素。不同酶系对T-2毒素的代谢速率不同，在人、比格犬、大鼠、小鼠肝微粒体中以酯酶代谢为主要贡献，而在猴肝微粒体中以CYP450酶系代谢为主要贡献。
第六章推测总结了T-2毒素及其主要代谢物的电喷雾质谱碎裂规律，以此为基础推测发现了6种可能的T-2毒素新代谢物，并推测了部分产物结构。
As an important example, T-2toxin has the most toxicity in presented tens oftrichothecenes mycotoxins. Due to its high toxicity, T-2toxin is considered as apotential chemical agent. It is also one of most dangerous origins for foodcontamination in nature. Currently, residents are greatly treatened by the widepollution of corns and crops caused by T-2toxin. It arouses the related researches onT-2toxin as one of the hot topics. Since T-2toxin metabolizes so rapid, its metabolitesraise the perseverative toxicity in vivo. Therefore, it is especially important todemonstrate the metabolism of T-2toxin.
Replacement, reduction and refinement animal testings are the core of the “3R”movement, which is gradually been widely accepted by the international community.Considering that the liver is the main site of drug and toxin metabolism andbioactivation, the in vitro surrogant experimental system based on liver, i.e., the livermicrosomes and hepatocytes, has wide applications for the researches on exogenousmetabolism and relevant toxicology in the“3R”movement with unique advantages andcharacteristics.
The aim of this dissertation is to investigate liver microsomes-based in vitrometabolism of T-2toxin, includes the inter-species differences of T-2txoin in livermicrosomes metabolism, especially the metabolic differences in human and severalanimal models, and metabolic effect of different enzyme systems. We expect it canprovide experimental data and scientific evidence for the metabolic mechanism of T-2toxin, the relationship between metabolism and toxicity, and the risk assessment onhuman health and food safety.
This dissertation is divided into six chapters. Chapter1is the review ofliteratures, more than70papers are cited. In this chapter recent advances on analysis, in vitro and in vivo metabolisms of T-2toxin are summarized based on the greattoxicological importance of such a toxin.
Chapter2describes the preparation of two major metabolites of T-2toxin, HT-2toxin and3’-OH T-2toxin. After separation and purification, both substances arecharacterized by IR,1H NMR and LC-MS techniques. We used in vitro maize esterasetransformation method to convert T-2toxin to HT-2toxin, and the yield was beyond80%. This enzyme catalytic method has the features of site-directed catalysis, mildcondition and high yield. We then adopted in vitro liver S9fraction biotransformationmethod to convert T-2toxin to its hydroxylated product,3'-OH T-2toxin with a yieldhigher than30%. Both reference regents afforded the material base for furtherresearches.
On this basis, in Chapter3, we developed several LC-MS/MS methods forsimultaneously quantitative determination of T-2toxin and its major metabolites indifferent matrices, they are, T-2toxin and3’-hydroxy-T-2toxin in rat S9fraction afteradministrated sodium pentobarbital, T-2toxin and its five metabolites in livermicrosomes and rat blood. The methods were fully validated, simple and rapid. Theparameters such as specificity, recovery, matrix effect, precision and accuracy were allmeet the requirements for bioanalysis. Such methods can be further applied in in vitrometabolic reasearches with good potential.
Chapter4demonstrates the in vitro metabolism studies of T-2toxin. We foundspecies differences in T-2toxin metabolism in liver microsomes. The descendingorder of intrinsic hepatic clearance rates for T-2toxin was human, mouse, monkey,dog and rat, but the hepatic clearance rates was from mouse, monkey, rat, dog down tohuman. The affinity and enzymatic turnover for T-2toxin were varied in differentanimal species.
Chapter5is the in vitro metabolism of T-2in different enzyme systems. We foundthat multiple cytochrome P450(CYP) isoenzyme were involved in T-2toxinmetabolism, including CYP3A4, CYP2E1, CYP1A2, CYP2C9, CYP2B6, CYP2D6and CYP2C19. CYP3A4isoenzyme was the predominant enzyme contributing to T-2 toxin metabolism and the major products were the hydroxylation products. Livermicrosomal esterase played an important role for T-2toxin in liver metabolism, andthe predominant product was HT-2toxin. The contributions originated from differentenzymes were of significant difference for the metabolic rate of T-2toxin. Theesterases played key role in T-2toxin metabolism in human, dog, rat and mousemicrosomes, and CYP450enzymes in monkey microsome.
Chaper6we employed electrospray ionization mass spectrometry in thecombination of Q-TOF MS and iontrap MS, and summarized the fragmentation rulesof T-2toxin and its main metabolites. Further, we also demonstrated that there weresix new metabolites related to T-2toxin, and we predicted the structures of suchmetabolites based on previous fragmentation rules.
以替代(replacement)、减少(reduction)和优化(refinement)动物试验为核心的“3R”运动逐渐被国际社会广泛接受。肝脏是药物毒物最重要的代谢器官，是生物转化的主要场所。以肝脏为基础的体外替代实验，如肝微粒体和肝细胞，在“3R”运动中起着重要的作用，其以特有的优势和特点在外源性物质代谢和毒性的研究中得到广泛应用。
本论文即旨在研究基于肝微粒体的T-2毒素的体外代谢，包括T-2毒素在肝微粒体中代谢的种属差异性，特别是T-2毒素在人肝微粒体中的代谢行为及和动物之间的代谢差异性，研究不同酶系对T-2毒素的代谢作用，期望为T-2毒素代谢机理、代谢与毒性的关系以及与人类健康的风险评估、食品安全研究等提供实验资料和科学依据。
本论文共分为六章，第一章为文献综述，引述文献70余篇，主要论述了近年来T-2毒素在分析方法、体内外代谢等方面的研究进展。
第二章为T-2毒素的两种代谢物即HT-2毒素、3’-OH T-2毒素的参考品制备部分。在分离纯化基础上，对之进行了结构表征；
采用玉米酯酶对T-2毒素进行特异性转化，制备HT-2毒素，产率高达80%以上，该酶催化方法具有定向催化、条件温和及产率高等特点；采用体外肝S9体系生物转化的方法，将T-2毒素定向转化为3’-OH T-2毒素，产率达30%以上。为后续的研究提供了物质基础；
在此基础上，第三章建立了基于液相色谱-质谱技术的T-2毒素及其主要代谢物的同时定量分析检测方法。包括T-2毒素及3’-OH T-2毒素在苯巴比妥诱导的大鼠肝S9中的定量检测方法，及T-2毒素及其五种代谢物在肝微粒体和全血中的分析检测方法。所建方法简单快速，灵敏度高，其回收率、精密度和准确度均符合生物样品定量分析的要求，展示了其用做体内外代谢动力学的良好应用前景；
第四章的体外代谢研究表明，T-2毒素的肝微粒体代谢存在种属差异性，肝固有清除率依次为人＞小鼠＞猴＞比格犬＞大鼠，然而肝清除率的顺序为小鼠＞猴＞大鼠＞比格犬＞人；不同种属肝微粒体对T-2毒素的亲和力和代谢能力存在差异。
第五章为T-2毒素在不同酶体系的体外代谢研究。在人肝微粒体中，多种细胞色素P450（CYP）同工酶参与了T-2毒素的代谢，包括CYP3A4、CYP2E1、CYP1A2、CYP2C9、CYP2B6、CYP2D6、CYP2C19，其中CYP3A4为主要的代谢同工酶，主要以羟基化产物为主；肝微粒体中酯酶对T-2毒素代谢作用明显，主要产物为HT-2毒素。不同酶系对T-2毒素的代谢速率不同，在人、比格犬、大鼠、小鼠肝微粒体中以酯酶代谢为主要贡献，而在猴肝微粒体中以CYP450酶系代谢为主要贡献。
第六章推测总结了T-2毒素及其主要代谢物的电喷雾质谱碎裂规律，以此为基础推测发现了6种可能的T-2毒素新代谢物，并推测了部分产物结构。
As an important example, T-2toxin has the most toxicity in presented tens oftrichothecenes mycotoxins. Due to its high toxicity, T-2toxin is considered as apotential chemical agent. It is also one of most dangerous origins for foodcontamination in nature. Currently, residents are greatly treatened by the widepollution of corns and crops caused by T-2toxin. It arouses the related researches onT-2toxin as one of the hot topics. Since T-2toxin metabolizes so rapid, its metabolitesraise the perseverative toxicity in vivo. Therefore, it is especially important todemonstrate the metabolism of T-2toxin.
Replacement, reduction and refinement animal testings are the core of the “3R”movement, which is gradually been widely accepted by the international community.Considering that the liver is the main site of drug and toxin metabolism andbioactivation, the in vitro surrogant experimental system based on liver, i.e., the livermicrosomes and hepatocytes, has wide applications for the researches on exogenousmetabolism and relevant toxicology in the“3R”movement with unique advantages andcharacteristics.
The aim of this dissertation is to investigate liver microsomes-based in vitrometabolism of T-2toxin, includes the inter-species differences of T-2txoin in livermicrosomes metabolism, especially the metabolic differences in human and severalanimal models, and metabolic effect of different enzyme systems. We expect it canprovide experimental data and scientific evidence for the metabolic mechanism of T-2toxin, the relationship between metabolism and toxicity, and the risk assessment onhuman health and food safety.
This dissertation is divided into six chapters. Chapter1is the review ofliteratures, more than70papers are cited. In this chapter recent advances on analysis, in vitro and in vivo metabolisms of T-2toxin are summarized based on the greattoxicological importance of such a toxin.
Chapter2describes the preparation of two major metabolites of T-2toxin, HT-2toxin and3’-OH T-2toxin. After separation and purification, both substances arecharacterized by IR,1H NMR and LC-MS techniques. We used in vitro maize esterasetransformation method to convert T-2toxin to HT-2toxin, and the yield was beyond80%. This enzyme catalytic method has the features of site-directed catalysis, mildcondition and high yield. We then adopted in vitro liver S9fraction biotransformationmethod to convert T-2toxin to its hydroxylated product,3'-OH T-2toxin with a yieldhigher than30%. Both reference regents afforded the material base for furtherresearches.
On this basis, in Chapter3, we developed several LC-MS/MS methods forsimultaneously quantitative determination of T-2toxin and its major metabolites indifferent matrices, they are, T-2toxin and3’-hydroxy-T-2toxin in rat S9fraction afteradministrated sodium pentobarbital, T-2toxin and its five metabolites in livermicrosomes and rat blood. The methods were fully validated, simple and rapid. Theparameters such as specificity, recovery, matrix effect, precision and accuracy were allmeet the requirements for bioanalysis. Such methods can be further applied in in vitrometabolic reasearches with good potential.
Chapter4demonstrates the in vitro metabolism studies of T-2toxin. We foundspecies differences in T-2toxin metabolism in liver microsomes. The descendingorder of intrinsic hepatic clearance rates for T-2toxin was human, mouse, monkey,dog and rat, but the hepatic clearance rates was from mouse, monkey, rat, dog down tohuman. The affinity and enzymatic turnover for T-2toxin were varied in differentanimal species.
Chapter5is the in vitro metabolism of T-2in different enzyme systems. We foundthat multiple cytochrome P450(CYP) isoenzyme were involved in T-2toxinmetabolism, including CYP3A4, CYP2E1, CYP1A2, CYP2C9, CYP2B6, CYP2D6and CYP2C19. CYP3A4isoenzyme was the predominant enzyme contributing to T-2 toxin metabolism and the major products were the hydroxylation products. Livermicrosomal esterase played an important role for T-2toxin in liver metabolism, andthe predominant product was HT-2toxin. The contributions originated from differentenzymes were of significant difference for the metabolic rate of T-2toxin. Theesterases played key role in T-2toxin metabolism in human, dog, rat and mousemicrosomes, and CYP450enzymes in monkey microsome.
Chaper6we employed electrospray ionization mass spectrometry in thecombination of Q-TOF MS and iontrap MS, and summarized the fragmentation rulesof T-2toxin and its main metabolites. Further, we also demonstrated that there weresix new metabolites related to T-2toxin, and we predicted the structures of suchmetabolites based on previous fragmentation rules.
引文
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[10]Dall Asta C,Galaverna G, Biancardi A, et al Simultaneous liquidchromatography–fluorescence analysis of type A and type B trichothecenes asfluorescent derivatives via reaction with coumarin-3-carbonyl chloride[J]. JChromatogr A,2004,1047:241–247
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[12] Pascale M, Panzarini G, Visconti A,Determination of HT-2and T-2toxins inoats and wheat by ultra-performance liquid chromatography with photodiode arraydetection [J].Talanta2012,89:231–236
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[14] Schothorst RC, Jekel AA, Determination of trichothecenes in beer by capillarygas chromatography with flame ionisation detection [J]Food Chem,2003,82:475–479
[15] Berthiller F, Schuhmacher R, Buttinger G,et al Rapid simultaneous determinationof major type A-and B-trichothecene as well as zearalenone in maize by highperformance liquid chromatography–tandem mass spectrometry[J].J Chromatogr A2005,1062:209–216
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