Molecular mechanisms of colon cancer chemoprevention: Studies on the potential of intestinal fermentation products to induce glutathione S-transferases in colonic epithelium cells

营养因素可能会促进或阻止结直肠癌的发生，延缓这一过程。在膳食纤维的肠道植物群发酵过程中会形成一些保护性化合物，如丁酸盐。在非转化细胞中，丁酸盐被用作能量来源。在转化细胞中，它促进凋亡和分化，抑制增殖并诱导谷胱甘肽S-转移酶（GST）活性。GST是一个II相酶超家族，可以消除癌症风险因素。我们已经表明，4-羟基壬烯醛（HNE）的脂质氧化产物的遗传毒性作用，在细胞中已被丁酸盐预处理，并增加了GST 1的水平降低。初步研究结果显示，对HNE高度特异的GSTA 4 -4也可能是可诱导的。在谷胱甘肽（GSH）耗竭的细胞中，HNE的遗传毒性增强。因此，结肠细胞对这种癌症风险因素的易感性取决于它们与GSH结合的能力。因此，高发酵性膳食纤维的营养干预可以通过诱导GST来保护。由于对非转化的人结肠细胞中的这种机制知之甚少，因此本提案的目的是评估丁酸盐是否在非肿瘤结肠细胞中诱导GST。用丁酸盐处理原代分离的结肠细胞，用新的分子生物学方法研究GST的诱导和耐药的前向危险因素。这些结果将首次揭示这种化学保护机制是否可以在非转化的人类细胞中发挥作用。

Nutritional factors may enhance or prevent colorectal carcinogenesis retard the process. Some protective compounds, such as butyrate, are formed during gut flora fermentation of dietary fibre. In non-transformed cells, butyrate is utilised as an energy source. In transformed cells, it promotes apoptosis and differentiation, inhibits proliferation and induces glutathione S-transferase (GST) activity. GSTs are a superfamily of phase II enzymes that can detoxify cancer risk factors. We have shown that the genotoxic effects of 4-hydroxynonenal (HNE) a product of lipid oxidation, are decreased in cells which have been pretreated with butyrate and have increased levels of GSTP1. Preliminary findings show that GSTA4-4, which is highly specific for HNE, may also be inducible. In cells depleted of glutathione (GSH), HNE's genotoxicity is enhaced. Thus, the susceptibility of colon cells to this cancer risk factor depends on their capacity to conjugate with GSH. Consequently, nutritional intervention with highly fermentable dietary fibre could be protective by inducing GST's. Since, little is known about such mechanisms in non-transformed human colon cells, it is the aim of this proposal is to assess whether butyrate induces GST in non-tumor colon cells. Primary isolated colon cells will be treated with butyrate and the induction of GSTs and resistence forward risk factors, will be studied using a new methods of molecular biology. The results will provide first insights into as to whether this mechanism of chemoprotection could play a role in non-transformed human cells.