Objective. —To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. Design. —A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. Setting. —Seven dermatology clinics in the eastern United States. Patients. —A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. Interventions. —Oral administration of 200 μg of selenium per day or placebo. Main Outcome Measures. —The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. Results. —After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR, 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. Conclusions. —Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=412293&pdfFileName=jama_276_24_027.pdf

Effects of Selenium Supplementation for Cancer Prevention in Patients With Carcinoma of the Skin: A Randomized Controlled Trial

Increases in the intracellular levels of reactive oxygen species (ROS), frequently referred to as oxidative stress, represents a potentially toxic insult which if not counteracted will lead to membrane dysfunction, DNA damage and inactivation of proteins. Chronic oxidative stress has numerous pathological consequences including cancer, arthritis and neurodegenerative disease. Glutathione-associated metabolism is a major mechanism for cellular protection against agents which generate oxidative stress. It is becoming increasingly apparent that the glutathione tripeptide is central to a complex multifaceted detoxification system, where there is substantial inter-dependence between separate component members. Glutathione participates in detoxification at several different levels, and may scavenge free radicals, reduce peroxides or be conjugated with electrophilic compounds. Thus, glutathione provides the cell with multiple defences not only against ROS but also against their toxic products. This article discusses how glutathione biosynthesis, glutathione peroxidases, glutathione S-transferases and glutathione S-conjugate efflux pumps function in an integrated fashion to allow cellular adaption to oxidative stress. Co-ordination of this response is achieved, at least in part, through the antioxidant responsive element (ARE) which is found in the promoters of many of the genes that are inducible by oxidative and chemical stress. Transcriptional activation through this enhancer appears to be mediated by basic leucine zipper transcription factors such as Nrf and small Maf proteins. The nature of the intracellular sensor(s) for ROS and thiol-active chemicals which induce genes through the ARE is described. Gene activation through the ARE appears to account for the enhanced antioxidant and detoxification capacity of normal cells effected by many cancer chemopreventive agents. In certain instances it may also account for acquired resistance of tumours to cancer chemotherapeutic drugs. It is therefore clear that determining the mechanisms involved in regulation of ARE-driven gene expression has enormous medical implications.

Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress

The antioxidants of human extracellular fluids.

Tissue-specific functions of individual glutathione peroxidases.

There are a number of components present in soybeans that exert a negative impact on the nutritional quality of the protein. Among those factors that are destroyed by heat treatment are the protease inhibitors and lectins. Protease inhibitors exert their antinutritional effect by causing pancreatic hypertrophy/hyperplasia, which ultimately results in an inhibition of growth. The lectin, by virtue of its ability to bind to glycoprotein receptors on the epithelial cells lining the intestinal mucosa, inhibits growth by interfering with the absorption of nutrients. Of lesser significance are the antinutritional effects produced by relatively heat stable factors, such as goitrogens, tannins, phytoestrogens, flatus-producing oligosaccharides, phytate, and saponins. Other diverse but ill-defined factors appear to increase the requirements for vitamins A, B12, D, and E. The processing of soybeans under severe alkaline conditions leads to the formation of lysinoalanine, which has been shown to damage the kidneys of rats. This is not generally true, however, for edible soy protein that has been produced under milder alkaline conditions. Also meriting consideration is the allergenic response that may sometimes occur in humans, as well as calves and piglets, on dietary exposure to soybeans.

Implications of antinutritional components in soybean foods

The sites of synthesis of extracellular (E) glutathione peroxidase (GPX), a unique selenoglycoprotein present in plasma, are not known. To investigate the possibility that the kidney is the main source for the plasma GPX, we examined GPX activities and selenium concentrations in the plasma of patients with renal failure on dialysis and nephrectomized patients before and after kidney transplantation. Plasma GPX activities in these patients were 42, 22, and 180% of normal EGPX activity, respectively, whereas plasma Se levels were within the normal range. Twenty-four hours after nephrectomy of anesthetized rats, plasma GPX activity was 30.0 +/- 6.4% of the activity at zero time. Northern hybridization analysis of eight human tissues probed with EGPX and cellular glutathione peroxidase (CGPX) cDNA revealed that the ratio of EGPX to CGPX was highest in the kidney. cRNA in situ hybridization studies on kidney slices showed that only proximal tubular epithelial cells and parietal epithelial cells of Bowman's capsule contained EGPX transcripts. Caki-2, a proximal tubular renal carcinoma cell line, makes and actively secretes EGPX. Taken together, these results strongly suggest that kidney proximal tubular cells are the main source for GPX activity in the plasma.

Human kidney proximal tubules are the main source of plasma glutathione peroxidase

The official first action AOAC fluorometric method for selenium in plants, 3.074-3.078, has been modified to simplify the method and to make it more accurate. The digestion time has been increased from 15 to 30 min past the appearance of perchloric acid fumes to better assure complete oxidation of all forms of selenium to selenite. Preparation of the 2,3-diaminonaphthalene solution, the reagent used for fluorometric analysis, has been changed so that the reagent is stable for several weeks; in the previous writeup, this solution had to be prepared daily. Special equipment (micro-Kjeldahl flasks with ground glass joints) has been eliminated and cyclohexane has been substituted for decahydronaphthalene. The modified method is convenient and applicable to a wide range of materials; it yields results comparable to those from the official method.

Modification of the official fluorometric method for selenium in plants

Identification of a major selenium excretory product in rat urine

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.510270322

Ivan S. Palmer

Papers

Human kidney proximal tubules are the main source of plasma glutathione peroxidase

Modification of the official fluorometric method for selenium in plants

Identification of a major selenium excretory product in rat urine

Plasma selenium in patients with cirrhosis

Trimethylselenonium ion as a general excretory product from selenium metabolism in the rat.