Hydroxylation, Oxidation And Glutathionyl Conjugation Of Polychlorinated Biphenyls3,15and77and Their Major Metabolites Identification

The problem of persistent organic pollution is related to the major issues of human survival and economic sustainability.As persistent organic pollutants, PCBs are presence in the global,difficult to degrade,long-range transport,bioaccumulation, carcinogenicity mutagenicity,and other characteristics.Environmental release of PCBs and serious toxic effects have been subject to a high degree of international concern. Although many studies have revealed the toxic effects of PCBs and the toxic mechanism of PCBs.But there are still a lot of mechanism yet to be discovered or fully understood clearly.PCBs have been metabolismed by the enzyme in vivo, resulting in a variety of highly active metabolites.However, due to the complexity of the metabolism of the PCBs, the structure of the metabolites and not completely understand clearly. Thus, the study of PCBs metabolites of great significance not only for understanding their chemical nature,and contribute to a comprehensive and in-depth understanding of its real mechanism of toxicity of the parent PCBs.In this thesis,based on in vitro metabolism of a model,three PCBs monomer hydroxylation, oxidation,the product of the glutathione adduct and its metabolites,qualitative and quantitative detection.The main work of this paper is as follows: (1)、The use of oxidation,reduction,Suzuki,coupling reaction of synthesis of polychlorinated biphenyls and their metabolites and the structures were identified.(2)、Extracted from male SD rats, the microsomal protein concentration was determined by Coomassie brilliant blue kit.In vitro metabolic model-bioassay,PCB15, PCB77metabolism,metabolites of the corresponding pre-treatment,HPLC,LC-MS identification of the structure.According to the structure of the metabolites,suggesting their possible metabolic pathways, and structure-activity comparison.(3)、PCB quinones and glutathione reaction, HPLC, LC-MS identification of the structure. According to the structure of the metabolites, suggesting its possible priority metabolic pathways and structure-activity comparison.This article draw the following conclusions ultimately:(1)、with the Microsomal/NADPH reduction system, PCBs can generate a single hydroxy and dihydroxy metabolites. With the increase of the number of chlorine atoms,CYP-450catalyzed hydroxylation rate reduced, PCB3was fully metabolized, about half of the PCB15was metabolized and PCB77was resistant to metabolize.(2)、Hydroquinone oxidized to quinones experiments show that under different oxidation conditions PCB15-HQ oxidation PCB15-Q rate is higher than the PCB3-HQ oxidation of PCB3-Q.(3)、the conjugation reaction of the chlorine on the quinone ring with glutathione was suggested that the Michael addition reaction has priority compare with displacement reaction in the conjugation of PCB15-Q with GSH.