Characterization of biological functions of food-derived hydrophobic materials and endogenous protection mechanism.

异源生物代谢酶在调节化学致癌物的毒性、氧化损伤、诱变和肿瘤效应方面发挥着重要作用。越来越多的证据表明，诱导第二相解毒酶，如谷胱甘肽S转移酶(GSTs)，可以防止毒性和化学致癌，特别是在起始阶段。谷胱甘肽转移酶是一类催化还原型谷胱甘肽(GSH)的硫醇与多种亲电试剂发生亲核加成的酶。此外，GST与各种芳香族疏水化合物具有不同的亲和力。现在人们普遍认为GST至少由五个不同的基因家族编码。四个基因家族(α，μ，π类和θ类)编码胞质GST，而第五个基因家族编码微粒体形式的酶。已有研究表明，GST的诱导与肿瘤的发生率和多发性有关。…的诱导据报道，更多的2相酶，如GSTs，被各种不同的化学试剂所激发，包括Michael反应受体、二酚类、苯二酚、异硫氰酸酯、过氧化氢、邻二硫醇等。除了少数例外，这些试剂都是亲电性的，因此，这些诱导剂中的许多都是第二相解毒酶的底物。在本项目中，我们研究了参与诱导第二相解毒酶的分子机制，并发现p类GST同工酶(GST P1)的诱导至少部分归因于蛋白酶体依赖的蛋白质周转调节机制的破坏。蛋白酶体是一种能选择性降解细胞内蛋白质的多亚基复合酶。这些酶去除的大部分蛋白质都被泛素化标记为要破坏。蛋白酶体通过信号介导的关键酶和调节蛋白的蛋白分解，在控制细胞过程中发挥作用，如新陈代谢和细胞周期。它还通过清除异常蛋白在应激反应中发挥作用，并通过产生抗原肽在免疫反应中发挥作用。因此，我们的发现表明，蛋白酶体的下调可能代表了抗癌化学物质的一个重要的间接作用，这可能有助于它们对慢性病的保护作用。较少

Xenobiotic metabolizing enzymes play a major role in regulating the toxic, oxidative damaging, mutagenic, and neoplastic effects of chemical carcinogens. Mounting evidence has indicated that the induction of phase 2 detoxification enzymes, such as glutathione S-transferases (GSTs), results in protection against toxicity and chemical carcinogenesis, especially during the initiation phase. The GSTs are a family of enzymes that catalyze the nucleophilic addition of the thiol of reduced glutathione (GSH) to a variety of electrophiles. In addition, the GSTs bind with varying affinities to a variety of aromatic hydrophobic compounds. It is now generally accepted that the GSTs are encoded by at least five different gene families. Four (classes α, μ, π, and θ) of the gene families encode the cytosolic GSTs, whereas the fifth encodes a microsomal form of the enzyme. It has been shown that the induction of GST is associated with the reduced incidence and multiplicity of tumors. The induction of … More phase 2 enzymes, such as GSTs, is reported to be evoked by an extraordinary variety of chemical agents, including Michael reaction acceptors, diphenols, quinones, isothiocyanates, peroxides, vicinal dimercaptans, and others. With few exceptions, these agents are electrophiles, and accordingly, many of these inducers are substrates for the phase 2 detoxification enzymes. In this project, we investigated the molecular mechanism involved in the induction of phase 2 detoxification enzymes and found that the induction of class p GST isozyme (GST P1) was, at least in part, attributable to the disruption of the proteasome-dependent regulatory mechanism of the protein turnover. The proteasome is a large multisubunit protease complex that selectively degrades intracellular proteins. Most of the proteins removed by these proteases are tagged for destruction by ubiquitination. Proteasome has a role to play in controlling cellular processes, such as metabolism and the cell cycle, through the signal-mediated proteolysis of key enzymes and regulatory proteins. It also operates in the stress response by removing abnormal proteins and in the immune response by generating antigenic peptides. Our findings therefore suggest that down-regulation of proteasome may represent an important indirect action of anticarcinogenic chemicals that can contribute to their protective effects against chronic diseases. Less