Characterization of the rat preneoplastic cell induction with glutathione S-transferase P form, GST-P,as marker enzyme

对癌前标志酶GST-P的生理功能、基因表达及对癌前病变细胞的诱导作用的研究结果表明：1.多种GST底物在高GSH浓度下被有效地非酶偶联，表明癌前病变细胞和肿瘤不仅是酶激活的，而且是非酶激活的。(参考文献1)2.利用融合蛋白技术制备了针对c-jun、c-fos等6种癌基因产物的抗体。大鼠肝癌前病变的免疫组织化学检测显示，GST-P的表达与癌基因产物的表达没有很好的相关性。(参考文献2)在过氧体增殖剂氯贝特、GST-P和过氧化体酶Enoyl-CoA水解酶诱导的大鼠癌前病变中，均为阴性。病灶内Alpha和Mu类GST水平也明显降低。参考文献3 4.急性期…在铁诱导的大鼠肾癌变过程中，GST-P的mRNA表达在给予氮三醋酸铁(15 mg/kg体重)后1~2小时即可观察到，提示GST-P可对抗致癌损伤和/或氧化应激。(参考文献4)5.制备了一种抗大鼠GSTP1-1的单抗，对该抗原的胰酶肽图显示了其C端198-208肽表位。(参考文献7)6.在Nrf2基因敲除的小鼠中，四种GST同工酶以及DT-黄递酶的诱导作用在丁化羟基苯甲醚喂养下丧失，其中Nrf2是珠蛋白基因的反式作用因子。结果表明，该因子与包括小鼠PI类GSTMII在内的II相解毒酶的基因表达密切相关。(参考文献11)7.物理化学方法表明，大鼠GST-P和人GSTP1-1的PI类酶的疏水亚基(H位)比Alpha类和Mu类GSTs低，这表明PI类对丙烯醛和羟基烯类等弱亲电性物质具有选择性。同时，PI类GST和肿瘤细胞在致癌过程中的宿主防御作用将被明确。较少

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 … More 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