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

对肿瘤前标记酶GST-P的生理功能、基因表达及诱导肿瘤前细胞的研究有如下结果：在高GSH浓度下，多种GST底物均被GSH有效地非酶结合，这表明肿瘤前细胞和肿瘤不仅被酶激活，而且被非酶激活。(ref . 1) 2。采用融合蛋白技术制备了c-JUN、c-FOS等6种癌基因产物的特异性抗体。大鼠肝脏肿瘤前病变的免疫组化检查显示GST-P的表达与癌基因产物的表达没有很好的相关性。(ref . 2) 3。在由过氧化物酶体增殖剂如氯贝酸盐、GST-P和烯酰辅酶a水解酶（一种过氧化物酶体酶）诱导的大鼠肿瘤前灶中，呈阴性。α和Mu类GST水平在病灶中也有所下降。(Ref.3) 4。在铁诱导的大鼠肾癌的急性期，早在给药后1 - 2小时（15mg /Kg体重），GST-P mRNA就升高，提示GST-P对致癌损伤和/或氧化应激有一定的抑制作用。(Ref.4) 5。制备了大鼠GSTP1-1的单克隆抗体，并对其进行了色氨酸肽定位，发现其c端198-208肽表位。(Ref.7) 6。在Nrf2基因敲除的小鼠中，四种GST同位酶以及DT-diaphorase的诱导性在丁基羟基茴香醚喂养中丧失，其中Nrf2是珠蛋白基因的反式作用因子。结果表明，该因子与小鼠Pi类GSTMII等II期解毒酶的基因表达密切相关（文献11）7。理化分析表明，与α和Mu类gst相比，大鼠GST-P和人GSTP1-1的Pi类酶的疏水亚位点（h位点）非常低，表明Pi类酶对弱亲电试剂如丙烯醛和羟基醛具有选择性。(手稿提交)。同时阐明Pi类GSTs和肿瘤细胞对致癌损伤的宿主防御作用。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