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Establishment of "non-sepcific type isoenzyme expression rule for Phase II drug-metabolizing enzymes during chemical carcinogenesis".

建立“化学致癌过程中II相药物代谢酶非特异性同工酶表达规律”。

基本信息

批准号：
05807009
负责人：
SATOH Kimihiko
金额：
$ 1.22万
依托单位：
HIROSAKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

Taking into consideration of the non-specific type isoenzymic characteristics of the glutathione S-transferase P-form (GST-P), which was identified by us, together with those of many other tumor marker enzymes, we tried to propose "Non-specific type isoenzyme expression rule for the Phase II drug-metabolizing enzymes during chemical carcinogenesis". This hypothesis was, however, unacceptable to some jounal submitted. Nevertheless, following results were obtained in relation to the chemical carcinogenesis.1.Broad substrate specificity and inhibitor insensitive nature, which are characteristic of the non-specific type isoenzyme, were observed for the human glutathione S-transferase P1-1(pi) as well.2.It was observed that GST substrates, such as ethacrynic acid, CDNB,and especially acrolein, were rapidly conjugated with glutathione in the presence of high GSH concentrations, suggesting that the detoxication potentials of the preneoplastic and neoplastic cells are significanly activated non-enzymatically as well.3.In relation to the gene expression of GST-P,specific antibodies to the trans-acting factors, c-JUN,c-FOS and others were prepared by immunization of rabbits and chickens with fusion proteins obtained from construction of fusion protein expressionvectors of pGEX-3X.No apparent correlation was, however, observed between the expression of the two factors and the GST-Pprotein when analyzed by the immunochemical ABC ctaining method.4.The biochemical and immunochemical properties of a total of six GST fusion proteins of oncogene products, c-JUN,c-FOS,c-MYC and c-Ha-ras and receptor proteins, GR and PPAR,were examined. It was revealed that the fusions were highly aggregative and immunogenic to rabbits and chickens.P.S., GST-P is now widely used as a specific marker in the various aspects of chemical carcinogenesis. The authors are at present interested in the physiological functions of GST-P as well as the molecular mechanism of gene expression.

考虑到我们所鉴定的谷胱甘肽S-转移酶P型（GST-P）的非特异性同工酶特性，以及许多其他肿瘤标志酶的非特异性同工酶特性，我们试图提出“化学致癌过程中II相药物代谢酶的非特异性同工酶表达规律”。然而，提交的一些期刊认为这一假设是不可接受的。然而，在化学致癌方面，我们得到了以下结果：1.人谷胱甘肽S-转移酶P1-1（pi）也具有广泛的底物特异性和抑制剂不敏感性，这是非特异性同工酶的特征。在高浓度GSH存在下，GST-P迅速与谷胱甘肽结合，表明癌前和肿瘤细胞的解毒潜力也被显著地非酶促激活。3.与GST-P基因表达相关，反式作用因子的特异性抗体，用构建的pGEX-3X融合蛋白表达载体获得的融合蛋白免疫家兔和鸡，制备了c-JUN、c-FOS等，但用免疫组化ABC染色法分析，两者的表达与GST-P蛋白无明显相关性。检测了c-JUN、c-FOS、c-MYC和c-Ha-ras以及受体蛋白GR和PPAR。结果表明，该融合蛋白对兔和鸡具有高度的聚集性和免疫原性。GST-P作为一种特异性标记物，广泛应用于化学致癌的各个方面。作者目前对GST-P的生理功能以及基因表达的分子机制感兴趣。