DIETARY REGULATION OF BIOCHEMICAL/MOLECULAR CHANGES IN CARCINOGEN RESISTANT CELLS

我们研究的主要重点是探讨与致癌物耐药性相关的生化和分子变化。通过持续暴露于苯并[a]芘（BP），我们开发了一系列抗癌细胞。这些细胞是研究由环境致癌物和外源物引起的早期生化和分子变化的模型，这些变化可能预防癌症。我们的抗BP细胞也能抵抗DMBA。据我们所知，这是第一次系统地研究致癌物质抵抗的整体机制，包括致癌物质的外排、激活和解毒。虽然某些解毒酶，谷胱甘肽-s转移酶，谷胱甘肽过氧化物酶和谷胱甘肽还原酶不变，但在BP抗性细胞中观察到还原型谷胱甘肽水平显著增加。我们的观察表明，氧化还原介导的途径级联可能参与致癌物抗性。因此，我们研究了戊糖磷酸分流的主要途径酶，葡萄糖-6-磷酸脱氢酶（G6PD）和脯氨酸循环的氧化还原偶联酶，吡咯啉5-羧酸还原酶（P5CR）。我们发现，与wt相比，BP耐药细胞中的G6PD和P5CR活性显著增加。我们提出，致癌物质耐药细胞的主要变化之一是氧化还原介导的机制。RNA表达的分子研究进一步支持了我们的假设。G6PD和P5CR的表达随抗性的增加而增加。氧化还原变化是否在预防乳腺肿瘤致癌物起始中起重要作用仍在我们目前的研究中。-抗致癌物，DMBA，类黄酮，G6PD，氧化/还原，

The primary focus of our study is to investigate the biochemical and molecular changes associated with carcinogen resistance. We developed a series of carcinogen-resistant cells by continuous exposure to benzo[a]pyrene (BP). These cells are a model for studying the early biochemical and molecular changes which may prevent cancer due to environmental carcinogens and xenobiotics. Our BP resistant cells are also co-resistant to DMBA. To our knowledge this is the first systematic examination of the overall mechanisms involved in carcinogen resistance, including carcinogen efflux, activation,and detoxification. Although certain detoxification enzymes, glutathione-s-transferase, glutathione peroxidase and glutathione reductase were unchanged, a significant increase in reduced glutathione levels was observed in BP resistant cells.Our observation suggested a redox mediated pathway cascade may be involved in carcinogen resistance. Therefore, we examined the major pathway enzyme of the pentose phosphate shunt, glucose-6-phosphate dehydrogenase (G6PD) and the redox coupling enzyme from the proline cycle, pyrroline 5-carboxylate reductase (P5CR).We found both G6PD and P5CR activities were markedly increased in BP resistant cells compared to WT.We proposed that one of the major changes in carcinogen resistant cells are in redox mediated mechanisms. Our hypothesis was further supported by molecular studies of RNA expression. The expression of G6PD and P5CR was increased with increasing resistance. Whether the redox changes are important in preventing carcinogen initiation in mammary tumors are under our current investigation. - Carcinogen resistance, DMBA, Flavonoids, G6PD, Oxidation/reduction,