| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1997: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000)
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| Research Abstract |
An investigation of the physiological functions and gene expression of a preneoplastic marker enzyme GST-P and the induction of the preneoplastic cells have pointed following results :
1.Various GST substrates were effectively GSH-conjugated non-enzymatically at high GSH concentrations, by which it was indicated that the preneoplastic cells and neoplastic are activated not only enzymatically but also non-enzymatically. (Ref.1)
2.Antibodies specific for six oncogene products, c-JUN,c-FOS and others, were prepared by fusion protein technology. Immunohistochemical examination of the rat hepatic preneoplastic lesions have shown that the GST-P expression was not correlated well with the expression of the oncogene products. (Ref.2)
3.In the rat preneoplastic foci inducible by peroxisome proliferators such as clofibrate, GST-P and enoyl-CoA hydrolase, a peroxisomal enzyme, are negative. The Alpha and Mu class GST levels were shown to be decreaced in the foci as well. (Ref.3)
4.In the acute stage
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of iron-induced rat renal carcinogenesis, GST-P mRNA increase was observed as early as one or two hours after administration of ferric nitrilotriacetate (15 mg/Kg body wt) suggesting the GST-P omdictopm against the carcinogenic insult and/or oxidative stresses. (Ref.4)
5.A monoclonal antibody to rat GSTP1-1 was prepared and tryptic peptide mapping of the antigen has shown up the C-terminal 198-208 peptide epitope. (Ref.7)
6.In the Nrf2 gene knockouted mice, inducibilities of the four GST isoenzymes as well as DT-diaphorase were lost against the butylated hydroxyanisole feeding, where Nrf2 is a trans-acting factor of globin genes. The result indicates the factor is closely related with the gene expression of Phase II detoxifying enzymes including mouse Pi class GSTMII.(Ref.11)
7.A physicochemical approach has revealed that the hydrophobic subsite (the H-site) of the Pi class enzymes of rat GST-P and human GSTP1-1 are very low as compared to Alpha and Mu class GSTs, suggesting that the Pi classes are selective for weak electrophiles such as acrolein and hydoxyalkenals. (manuscript submitted).
In a meanwhile, host-defensive roles of Pi class GSTs and the neoplastic cells agasint carcinogenic insult will be made clear. Less
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