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

外源性代谢酶在调节化学致癌物的毒性、氧化损伤、致突变和肿瘤效应中起主要作用。越来越多的证据表明，诱导第二阶段解毒酶，如谷胱甘肽S-转移酶（GST），导致对毒性和化学致癌作用的保护，特别是在起始阶段。GST是催化还原型谷胱甘肽（GSH）的硫醇与各种亲电试剂的亲核加成的酶家族。此外，GST以不同的亲和力与各种芳族疏水化合物结合。现在普遍认为GST由至少五个不同的基因家族编码。四个基因家族（α、μ、π和θ类）编码细胞质GST，而第五个基因家族编码该酶的微粒体形式。已经表明GST的诱导与肿瘤的发病率和多样性的降低相关。的诱导 关于我们 据报道，2相酶（例如GST）可由非常多的化学试剂诱发，所述化学试剂包括迈克尔反应受体（Michael reaction receptor）、二酚、醌、异硫氰酸酯、过氧化物、邻位二硫醇等。除了少数例外，这些试剂都是亲电试剂，因此，这些诱导剂中的许多是2期解毒酶的底物。在这个项目中，我们研究了参与诱导第2阶段解毒酶的分子机制，发现p类GST同工酶（GST P1）的诱导至少部分归因于蛋白质周转的蛋白酶体依赖性调节机制的破坏。蛋白酶体是一种大的多亚基蛋白酶复合物，选择性降解细胞内蛋白质。大多数被这些蛋白酶去除的蛋白质被标记为通过泛素化破坏。蛋白酶体通过信号介导的关键酶和调节蛋白的蛋白水解在控制细胞过程中发挥作用，例如代谢和细胞周期。它还通过去除异常蛋白质在应激反应中起作用，并通过产生抗原肽在免疫反应中起作用。因此，我们的研究结果表明，蛋白酶体的下调可能是抗癌化学物质的一个重要的间接作用，有助于其对慢性疾病的保护作用。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