| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2003: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Research Abstract |
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
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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
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