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Selenium in Nutrition and Toxicity Dr. Karin Hotz Jeannine Baumgartner ETH Laboratory of Human Nutrition Institute of Food, Nutrition and Health Overview … deficiency and overload … dietary reference intakes and sources … species: inorganic and organic compounds … absorption, metabolism & excretion … and its functions in selenoproteins … importance to human health Picture: www.buzzle.com 08.03.2011 1 Selenium as an essential trace element: symptoms of deficiency and overload Selenium deficiency Selenium overload Impaired muscle function Keshan disease (Se as causative cofactor) cardiomyopathy Kashin-Beck disease (Se as causative cofactor) Acute overdosing: garlic odor on the breath nausea stomach ache liver damage chronic overdosing: hair loss brittle fingernails neurological damage deforming arthritis pictures: www.wikipedia.org 08.03.2011 2 Dietary Reference Intakes Recommended daily intakes (SGE) children adolescents adults 25-60 μg/d 30-70 μg/d 30-70 μg/d (U.S. RDA: 55 μg/d) Safe upper limit (SGE) adults 400 μg/d (symptoms of chronic overload above 800 μg/d) narrow window between ingested amounts resulting in deficiency 08.03.2011 and those resulting in toxicity! 3 Dietary Reference Intakes and Sources Recommended daily intake of 30 μg found in: lobster tuna mussels kidney (calf) codfish oysters liver (cow) egg pasta pork meat eggs whole grain bread 08.03.2011 SGE 4 Dietary Reference Intakes and Sources n.d. n.d. n.d. n.d. n.d. n.d. Soil concentration, dietary intake and serum levels recommended intake 30-70 μg/d Dumont E. (2006) 12.10.2010 5 Dietary Reference Intakes and Sources Soil concentration, dietary intake and serum levels Upper safe limit 400 μg/l Dumont E. (2006) 12.10.2010 6 Selenium metabolism in plants Se2- (CH3)-Se-Cys accumulated in certain plants (CH3)-Se-Met phytovolatilization (detoxification) (CH3)2Se 08.03.2011 Dumont E. (2006) 7 Selenium metabolism in plants Se-accumulating plants normal: < 100 μg/g Se (dry weight) Se-accumulators: > 1000 μg/g Se (dry weight) garlic (allium sativum) pictures: www.wikipedia.org 12.10.2010 broccoli (brassica oleracea) common mushroom (agaricus bisporus) Dumont E. (2006) 8 Se species: inorganic and organic Se compounds Se2- selenide (Se-II) S selenite (SeIV) selenocysteine H selenoproteins (Se-Cys in active site) methylselenide Me-selenocysteine selenate (SeVI) Se-containing proteins dimethylselenide (e.g. Met replaced by Se-Met, no specific function for Se) selenomethionine 08.03.2011 Dumont E. (2006) 9 Se species: inorganic and organic Se compounds Bioavailability organic selenium species have a higher bioavailability than inorganic species picture: www.magen-darm-grippe.de Targeting depending on the species, Se is specifically targeted to functional compartments or unspecifically distributed between tissues picture: www.monetized.co.za 08.03.2011 10 Selenium metabolism in humans A) low Se intake SeO32- SeO32- Selenoproteins 2- GSH (Se-Cys in active site) H2Se Se-Cys Se-Met Se-Met methyltransferase Se-Cys demethylase SeO4 human body CH3SeH Yanghorbani 1999 Ip 1998 Brozmanova 2010 Wolffram 1989 08.03.2011 urine 11 Selenium metabolism in humans B) high Se intake SeO32- SeO32- Selenoproteins 2- GSH (Se-Cys in active site) H2Se Se-Cys Se-Met Se-Met Se-sugars methyltransferase Se-Cys demethylase SeO4 human body CH3SeH Se-Met-containing proteins (Se stores) (Se-Met incorporated instead of Met) Yanghorbani 1999 Ip 1998 Brozmanova 2010 Wolffram 1989 08.03.2011 (CH3)2Se (CH3)3Se+ breath urine 12 Physiological Function of Selenoproteins (Examples) R-O-H selenoprotein P glutathione peroxidases (GPx) antioxidants antioxidant, probably involved in Se-homeostasis R-O-O-H T4 iodothyronine deiodinases T3 NADP+ thioredoxin reductases oxidized thioredoxin reduced thioredoxin cell growth and survival needed for muscle function rT3 3,3’T2 NADPH selenoprotein W oxidized ascorbate reduced ascorbate DNA-bound spermatic selenoprotein may protect developing sperm mitochondrial capsule selenoprotein protects developing sperm from ox. damage, polymerizes into structural protein required for stability/motility of mature sperm selenophosphate synthetase required for selenoprotein synthesis Rayman 2000 08.03.2011 The importance of selenium to human health Immune function Viral infection Thyroid function Cardiovascular disease Cancer and chemoprevention 12.10.2010 14 Role of selenium in immune function Immune system Innate “nonadaptive” immunity humoral cellular Acquired ”adaptive” immunity humoral cellular Cytokines Macrophages Antibodies Lymphocytes - Interferon Granulocytes - Immunoglobulin - T-cell - Interleukins (eg. IL-3, IL-2, etc) - Neutrophils (eg. IgG, IgA, etc) - B-cell - Basophils - Eosinophils Natural-Killer (NK) cells Involvement of Se in immune system: • Increased activity of NK cells • Proliferation of T-cells • Increased interferon production • Increased interleukin receptors 12.10.2010 Figure: Modified from http://www.ndteducational.org/muellerslide2006txt.asp • Stimulation of vaccine-induced immunity • More antibody-producing B-cells • Macrophage and neutrophil activity Tinggi, 2007 15 ….proposed mechanisms Selenoproteins influence three broad areas of cell function an therefore affect immune function through: • Antioxidant activities • Thyroid hormone metabolism • Regulation of the activity of redox-active proteins Example: Neutrophil function - Neutrophils produce peroxi-derived radicals to kill invading microbes, but also the neutrophils themselves need to be protected from the radicals by the system. - Radical production and protection depends on GPx activity in neutrophils, which is impaired in Se-deficiency. Arthur, 2003 12.10.2010 16 Role of selenium in viral infection In Se-deficient mice harmless viruses can become virulent. ( e.g. coxsackie virus causing cardiomyopathy in Keshan disease) Se + Infection with virus Se - GPx Adequate GPx deficient ↑ Oxidative stress ↑↑↑ Oxidative stress Normal immune response Mild to no tissue damage Altered immune response Viral mutation Moderate to severe tissue damage Figure: Beck, 2001 Subjects supplemented with Se showed less mutations in poliovirus compared to placebo group. HIV patients are nearly 20 times more likely to die from HIV-related causes than those with adequate levels. And low Se levels in HIV-infected children are related to faster disease progression. Rayman, 2000 12.10.2010 17 Role of selenium in thyroid function Deiodinases are Se-containing enzymes playing important roles in thyroid hormone metabolism. Low plasma T3:T4 ratios found in people with low Se intake. A combined deficiency of iodine and selenium is associated with severe endemic myxedematous cretinism (in Democratic Republic of Congo). Se supplementation in elderly subjects decreased plasma thyroxine (T4) concentrations , increased deiodinase activity and improved conversion of the active hormone T3. Se Impaired thyroid hormone metabolism has adverse effects on function. Figure: Myxedematous endemic cretinism in the Democratic Republic of Congo 12.10.2010 immune Tinggi, 2008; Rayman, 2000 18 Role of selenium in cardiovascular disease (CVD) Increased production of ROS can cause oxidative stress and cause damage to cellular lipids, proteins and DNA, leading to CVD. Selenoproteins may help to combat oxidative modification of lipids and to reduce platelet aggregation. Epidemiological studies produced mixed findings (examples): 2 to 3-fold increase in CV morbidity and mortality in subjects with serum Se conc. below 45 µg/L compared to subjects above at baseline. Increased risk of ischaemic heart disease in Danish men with serum Se below 79 μg/L. Inverse association between toenail Se and risk of myocaridal infarction only in areas with the lowest Se status. Thus, effect maybe only apparent in populations of low Se status. Ebselen, a synthetic mimic of glutathione reductase showed cardio- protective effects in mice. Tinggi, 2008, Rayman 2000 12.10.2010 19 Role of selenium in chemoprevention Possible mechanisms of cancer prevention by selenium Mechanisms of Se From homepage of German Cancer Research Center 12.10.2010 20 …history of selenium in chemoprevention • In 1969 Shamberger found that his cancer patients had selenium blood levels only 60 to 80 % as high as non-cancer patients. • In 1977, Schrauzer reported that selenium intake in 27 countries was inversely correlated with breast cancer death rates. • Several human epidemiological studies found a statistically significant inverse relationship between Se level and risk of cancer overall, particularly in men. • Also early animal studies have shown that selenium added to the diet reduced cancer incidence. Tinggi, 2008, Rayman 2000 12.10.2010 21 Se in chemoprevention • In the first RCT, supplementation with selenized yeast (200 µg/day), predominantly in the form of selenomethionine (Se-Met) for 4 years, led to a reduction of nearly 50% in overall cancer morbidity (Clark, 1996). Average selenium intake of the study subjects 90 µg/day, well above levels needed for optimal selenoprotein activity. This suggests additional chemopreventive mechanisms. • Inorganic forms, such as selenite/selenate, were more effective than commonly used organic form Se-Met in fighting cancer. • Because cells can not distinguish Se-Met from essential amino acid methionine, it is incorporated into general body proteins. • However, inorganic Se is more toxic compared to organic Se forms. Brozmanova, 2010, Rayman 2000, Ip, 1998 12.10.2010 22 Methylselenocystein (Met-Se-Cys): Less toxic alternative • Is formed naturally in various plants grown on high selenium soil. • Met-Se-Cys rich foods have shown good anticancer activity, without excess tissue accumulation or toxicity. • Met-Se-Cys is converted into methylselenol (CH3SeH), which has been shown to be an active anticancer form of Se. Mechanism of action: Apoptosis and inhibition of angiogenesis. toxic methyl-transferase SeMC H2Se CH3SeH demethylase MSA And it is less toxic! (CH3)2Se breath 12.10.2010 Monomethylated Se compounds, SeMC and methylselenic acid (MSA), were shown to be more effective than other Se compounds in chemoprevention. MSA urine Brozmanova, 2010, Rayman 2000, Ip, 1998 23 Selenium in human health – A double-edged sword • Several organic and inorganic Se compounds have been investigated as Se supplements. Their safety and efficacy differ markedly because of their differential metabolic processing by the body. • The inorganic Se compound, sodium selenite, due to its prooxidant character, represents a promising alternative for cancer therapy. • However, this Se compound is highly toxic compared to organic Se forms. • To achieve chemopreventive effects, Se had to be given at Se levels 5-10 fold higher than what would be required for normal nutritional need. • Due to a broad interest in the positive effects of Se on human health and cancer therapy, studies investigating the negative effects such as toxicity and DNA damage are highly required. 12.10.2010 24 Literature Rayman M.P. (2000); The importance of selenium to human health. Lancet 356: 233-41 Dumont E., Vanhaecke F., Cornelis R. (2006); Selenium speciation from food source to metabolites: a critical review. Anal. Bioanal. Chem. 385: 1304-1323 www.sge-ssn.ch (homepage of SGE, “Schweizerische Gesellschaft für Ernährung”) Brozmanova J., Manikova D., Vlckova V., Chovanec M. (2010); Selenium: a double-edged sword for defense and offence in cancer. Arch. Toxicol. 84: 919-938 Ip, C. (1998); Lessons from Basic Research in Selenium and Cancer Prevention. J. Nutr. 128(11): 1845-1854 Janghorbani M., Xia Y., et. al. (1999); Metabolism of Selenite in Men with Widely Varying Selenium Status. J. Am. Coll. Nutr. 18(5), 462-469 Tinngi U (2008); Selenium: its role as antioxidant in human health. Environ Health Prev Med. 13:102-108 Arthur J.R, McKenzie RC, Beckett J (2003); Selenium in the Immune System. J. Nutr 133: 1457S-1459S Beck MA (2001); Antioxidants and Viral Infections: Host Immune Response and Viral Pathogenicity. J. Am College of Nutrition. 20(5), 384S-388S http://www.dkfz.de/en/tox/c010-2_projects/list_assays.html (homepage of German Cancer research Center) 08.03.2011 25