Selenium (Se) is an essential trace element. High levels of plasma Se and using Se supplements are associated with low cancer risk. Organic forms of Se, including Se-enriched cruciferous vegetables, are especially potent in this regard. We have hypothesized that the chemopreventive effect of Se is independent of glutathione peroxidase (Gpx), since effects are reported at Se levels above those that saturate the Gpx expression. We have generated a Gpx1/2-KO mouse line, with combined disruption of both Gpx1 and Gpx2 genes, which encode two intracellular Se-dependent Gpxs. These mice have ileocolitis and cancer, resembling increased cancer risks of human patients having either Crohn's disease (CD) or ulcerative colitis (UC). Thus, these mice are ideal to test our hypothesis on the role of Gpx1 and Gpx2 in Se-mediated chemoprevention. In this study, we plan to determine the following: 1. To determine whether Se supplementation, either as sodium selenite or in selenized Indian mustard, can prevent inflammation and gene mutations in Gpx1/2-KO mice. If so, it supports the notion that the anti-inflammatory and anti-mutagenic activity of Se is independent of Gpxs. 2. If Se-supplementation prevents inflammation and/or gene mutations, we will determine the long-term effect of Se on tumor load in the intestine. A positive result will support our hypothesis that the chemopreventive effect of Se is independent of Gpx1 and Gpx2. 3. If Se-supplementation does not prevent inflammation or gene mutations in the Gpx1/2-KO mice, it suggests that the Se effect is mediated through Gpxs. We will determine the effect of Se-supplementation on chemical-, dextran sulfate sodium, induced colitis in mice expressing wildtype Gpx1 and Gpx2 alleles. Upon completion of this study, we will understand whether Se can prevent inflammation and gene mutations in mice prone to have inflammatory bowel disease (IBD). We may provide answers to a) does organoselenium protect better than the inorganic Se? and b) does the chemopreventive effect of Se depend on Gpx1 and Gpx2? Our results can be used as basis for human clinical trials to use Se as therapeutic or chemopreventive agents for IBD and IBD-associated cancer.
| Lee, Dong-Hyun; Esworthy, R Steven; Chu, Christy et al. (2006) Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Cancer Res 66:9845-51 |
