Epidemiological studies, clinical intervention trials (including the trial with selenium-enriched yeast by Clark et al. JAMA 276, 1957, 1996) and assays in laboratory animals provide evidence for a protective role of selenium against the development of several cancers, including lung cancer. We have demonstrated that selenium in the form of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a promising chemopreventive agent in the A/J mouse lung tumor model induced with the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); under identical conditions, selenomethionine (SM), a component of selenium-enriched yeast, had no effect. The lack of an effect of SM suggests that other forms of selenium, or selenium-enriched yeast as a whole, are essential for lung cancer prevention; moreover, various species may respond differently to a given form of selenium. Therefore, in this study, we compared the chemopreventive efficacies of p-XSC with selenium-enriched yeast. Groups of 5-wk-old mice were fed either control diet or experimental diet containing p-XSC (5 or 10 ppm as selenium, equivalent to 20% and 40% maximum tolerated dose [MTD], respectively) or selenium-enriched yeast (5 or 10 ppm). Beginning at Wk 7, each mouse received NNK (3 mmol) in 0.1 ml cottonseed oil by intragastric intubation, once weekly for 8 wk. Twenty-six weeks after the first NNK administration, mice were killed and tumors in lung and forestomach were counted. p-XSC at 5 and 10 ppm doses significantly reduced lung tumor induction by NNK from 10.4 -/+ 6.0 (multiplicity) to 2.7 -/+ 1.5 (P < 0.001) and 1.8 -/+ 2.0 (P < 0.0001) respectively, whereas selenium-enriched yeast had no effect. p-XSC at 10 ppm also significantly reduced the incidence level from 96% to 68% (P < 0.01). The amounts of selenium that reach the target organ (lung) after dietary administration of p-XSC (326 -/+ 69 ng Se/g lung tissue) were significantly higher than that from selenium-enriched yeast (34 -/+ 8.5 ng Se/g lung tissue). However, the levels of selenium in plasma from selenium-enriched yeast (620 -/+ 54 ng Se/g plasma) were twofold higher than those from p-XSC (355 -/+ 85 ng Se/g plasma). In biochemical studies, p-XSC was shown to significantly inhibit formation of O6-methylguanine (O6-MG) and 7-methylguanine (7-MG) in the lungs and livers of mice treated with NNK. The lack of effect of selenium-enriched yeast on these lesions agrees with the results of the bioassay. Collectively, the results of this study clearly indicate that as a chemopreventive agent, p-XSC is superior to selenium-enriched yeast under the conditions of the present protocol. The inhibition of DNA methylation and the significantly higher retention of selenium from p-XSC as compared with selenium-enriched yeast in the target organ may in part account for the inhibition of lung tumorigenesis.

Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine‐β‐muricholic acid (Gly‐MCA) is an intestine‐specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly‐MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly‐MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly‐MCA decreased intestine‐derived ceramides by suppressing ceramide synthesis–related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly‐MCA, and a correlation was found between intestine‐derived ceramides and NASH severity. This study revealed that Gly‐MCA, an intestine‐specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly‐MCA a novel agent for the prevention and treatment of NASH.