- an essential trace element

2. - an essential trace element

3. Basics

4. What is selenium? • discoverer: Berzelius (1817) • occurrence in the earth‘s crust: 0.05 ppm • nonmetal (chalcogen) • close chemical relationship with sulphur • fields of application: semi-conductor technology/photo technique, medicine • essential trace element for humans and animals, possibly for plants as well

5. Close chemical relationship

6. Important inorganic selenium compounds Na2SeO3• 5 H2O Sodium selenite = an inorganic salt of selenium so-called sodium salt of selenous acid (as pentahydrate)

7. Selenium intake Selenium Selenium Selenium Selenium

8. Selenium intake in Europe SCF (2000): Opinion of the scientific committee on food on the tolerable intake level of selenium. SCF/CS/NUT/UPPLEV/25 final

9. Selenium intake in Europe Rayman MP (2000): The importance of selenium to human health. Lancet Vol 356, 233-241

10. Occurrence of selenium inorganic 1. in traces in sulfides: iron pyrites FeS2 chalcopyrites CuFeS2 zinc blende ZnS 2. in rare minerals 3. technical: lead chamber slurry (1817 Berzelius) 4. drinking water (selenite, selenate; e.g. < 2 µg/l) organic 1. protein-bound: vegetable: predominantly as SeMet animal: predominantly as SeCys

11. Daily kidney? Vegetableca. (µg): brussels sprouts 1 boletus 184 Bread, bakery products rye bread 3 pasta (containing eggs) 20 Grain rye 1 wheat bran 2 oat flakes 10 Meat, fish ca. (µg): liver (beef) 21 filet (beef) 35 trout 25 herring 43 kidney (beef) 112 Milk, eggs, milk products cow‘s milk 1 Camembert, 45% F.i.d.m. 3 Fruit banana 1 grape 2 (circa data on selenium in µg/100g) Elmadfa, Muskat, Fritzsche, (2004/05): Die große GU-Nährwertkalorientabelle, Neuausgabe

12. Selenium supply in Germany Medium daily selenium intake: 30 µg/day 41 µg/day  suboptimal supply: Ø 0.67 µg/kg body weight VERA-study: Selenium serum concentrations 83 µg/l 82 µg/l max. activity GPX: 95 µg/l lowest cancer incidence: > 121 µg/l  optimum intake: 1.5 µg/kg body weight Source: DAZ Nr. 11, 2005

13. Recommendations of the DGE (German Society for Nutrition) Age Selenium µg/day infants 0 to 4 months 5 - 15 4 to 12 months 7 - 30 children 1 to 4 years 10 - 40 4 to 7 years 15 - 45 7 to 10 years 20 - 50 10 to 15 years 25 - 60 Source: Deutsche Gesellschaft für Ernährung e. V.: "Selen - Schätzwerte für eine angemessene Zufuhr“ , 2000.

14. Recommendations of the DGE (German Society for Nutrition) Age Selenium µg/day adolescents 15 to 65 years 30 - 70 + adults pregnancy 30 - 70lactation 30 - 70 Source: Deutsche Gesellschaft für Ernährung e. V.: "Selen - Schätzwerte für eine angemessene Zufuhr“ , 2000.

15. Toxicology 1200 µg selenium / day LOAEL “Lowest observed adverse effect level” 850 µg selenium / day NOAEL “No observable adverse effect level” 300 µg selenium / day UL “Tolerable upper intake level” Source: SCF, (2000): Opinion of the scientific committee on food on the tolerable intake level of selenium. SCF/CS/NUT/UPPLEV/25 Final

16. Safe total daily intake Safe total daily intake according to age groups “Tolerable upper intake level” Age group UL (Tolerable upper intake level) 1 - 3 years60µg selenium / day 4 - 6 years90µg selenium / day 7 - 12 years130µg selenium / day 13 - 14 years200µg selenium / day 15 - 17 years250µg selenium / day adults 300µg selenium / day Source: SCF, (2000): Opinion of the scientific committee on food on the tolerable intake level of selenium. SCF/CS/NUT/UPPLEV/25 Final

17. Selenium metabolism Modified according to: Windisch, Gabler, Kirchgeßner, (1997): Umwelttoxikologie (VO 910.305) Systemkomponente “Tier”: Selen WS (2004/05)

18. How does selenium reach the protein? Modified according to: Windisch, Gabler, Kirchgeßner, (1997): Umwelttoxikologie (VO 910.305) Systemkomponente “Tier”: Selen WS (2004/05)

19. Distribution of selenium in the body Selenium content of human organs and body fluids: Source: Biesalski HK, Köhrle J, Schümann K, (2002): Vitamine, Spurenelemente und Mineralstoffe. Prävention und Therapie mit Mikronährstoffen. Georg Thieme Verlag, Stuttgart

20. Selenium deficiency situations Possible reasons of an absolute or relative selenium deficiency • reduced selenium supply • disturbed selenium intake • increased selenium losses • increased selenium demand • increased endogenous strain with radicals and peroxides • increased exogenous strain with noxa

21. Reduced selenium supply • nutritional conditions and habits - extremely unbalanced nutrition - vegetarians - vegans • parenteral nutrition • diets

22. Disturbed selenium intake • gastro-intestinal diseases • maldigestion, malabsorption, celiac disease

23. Increased selenium demand • pregnancy • lactation • high physical strain or stress • elder persons • immune deficiency

24. Increased selenium demand • chronical destructive diseases, above all tumour diseases • rheumatism-related diseases (arthritis, arthroses) • cardiovascular diseases (coronary heart disease, cardiomyopathy, atherosclerosis) • inflammatory diseases of the gastro-intestinal tract (pancreatitis, Crohn‘s disease, ulcerative colitis)

25. Increased exogenous strain with noxa • workplace • heavy metals (e.g. amalgam) • chemotherapy • radiotherapy • alcohol, nicotine

26. Diagnosis of the selenium status • The determination from the whole bloodhas been proven for the measurement of the selenium level. • Hair isn‘t that suitable as examination material as it‘s not actively involved inthe metabolism. • Special laboratories measure theselenium content as a matter of routine and relatively low-priced.

27. Selenium status Recommendations for laboratory analysis (Germany) Serum: Short-term parameter deficient < 65 μg/l = < 0.81 μmol/l normal 50 - 120 μg/l = 0.81 - 1.25 μmol/l optimal 101 - 135 μg/l = 1.26 - 1.71 μmol/l Whole blood: Long-term parameter deficient < 85 μg/l = < 1.06 μmol/l normal 60 - 120 μg/l = 1.06 - 1.50 μmol/l optimal 121 - 162 μg/l = 1.51 - 2.05 μmol/l Source: Gröber U, (2003): Selen. OM. Z. f. Orthomolekulare Medizin 4, 25-26

28. State of selenoprotein research 1973 - 2002 Selenoproteins with known enzymatic function: glutathione peroxidase thioredoxin reductase deiodase 2003 Selenogenome: human: 25 genes rodent: 24 genes drosophila: 4 genes C. elegans: 1 gene 2005 Selenoproteome: 30 - 70 forms Modified according to: Schomburg L, Schweizer U, Köhrle J, (2005): Selen und Selenoproteine. Humboldt Spektrum 3, 12-18

29. Selenium-containing proteins in humans Enzymes glutathione peroxidase thioredoxin reductase deiodase selenophosphate synthetase 2 Selenium-binding selenoprotein Pprotein Proteins with still selenoprotein W unexplained function several other selenoproteins Selenoproteins: Proteins, specifically containing selenocysteine

30. Selenium-containing proteins in humans muscle proteins globin other tissue proteins Proteins, containing non-specifically integrated selenium

31. Glutathione peroxidase • 1973 identified as selenoprotein • contains 4 Se-atoms, bound as selenocysteine in the active centre • can be found everywhere in the organism • catalytic activity: reduction of peroxides

32. Origin and effect of radicals UV-radiation elimination of foreign substances inflammations (phago-cytosis, PG-synthesis) metabolic processes O2-transport (Hb) reper-fusion X-rays damage of cell membraneDNA damage protein cross-linkingcell destruction

33. Glutathione peroxidase Peroxide detoxification by glutathione peroxidase GSH = reduced glutathione GSSG = oxidised glutathione E = enzyme

34. Glutathione peroxidases Function protect the organism from the toxicity of endogenous and exogenous peroxides

35. Glutathione peroxidases Selenium deficiencydecrease in enzyme activity oxidative destruction of biomolecules, cells and tissues involved in numerous human diseases and disorders where radicals have either a primary or secondary role, such as e.g. • atherosclerosis • cardiomyopathy • amyotrophic lateral sclerosis • rheumatism • infertility • cancer

36. Deiodases Function activation (T4 to T3) and deactivation (T4 to rT3) of thethyroid hormones provide appropriate levels of thyroid hormonesessential for growth, differentiation and metabolism

37. Deiodases Selenium deficiencydecrease in enzyme activity suboptimal (type-I and type-II-5’-deiodases) or supraoptimal levels of active T3 (type-III-5-deiodase) plays a role in various diseases, such as e.g. • Hashimoto‘s thyroiditis • H2O2-dependent destruction of thyroid due tocontinuous stimulation by TSH • disorders in fetal brain development

38. Thioredoxin reductases play a decisive role in regulation of transcription (transcription factors NF-κB and AP-1) are involved in DNA biosynthesis regulate the cellular redox status, have a bearing onthe redox status of GSH (glutathione) modulate folding (and consequently the function) of proteins have a large substrate range (Trx, H2O2, dehydro-ascorbate, proteins) Function

39. Thioredoxin reductases dysregulation of proliferation and differentiation of cells: is supposed to be part of the malignant transformation of cells is considered to be a lethal factorin theearly embryonic stage Selenium deficiencydecrease in enzyme activity total knockout of the enzyme

40. and cancer Tumour prevention

41. Selenium is effective on two levels 1. indirectly via incorporation into specific selenoproteins e.g. GPx 2. directly through built-up selenium metabolites e.g. methylselenol

42. Chemopreventive effect of selenium Fig. modified according to: Combs GF Jr, (1999): Chemopreventive mechanisms of selenium. Medizinische Klinik (Munich) 94 (Suppl. III), 18-24

43. Selenium has a tumour-preventive property Tumour-preventive effect verified in large studies • Qidong-study: Primary hepatic cancer(China 1985-1989, primary hepatic cancer, placebo-controlled, 20,847 probands) • Linxian-study: Esophageal cancer(China 1986-1991, esophageal cancer, 29,584 probands) • Clark-study

44. Selenium has a tumour-preventive property Clark-study Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Clark LC, Combs GF Jr, et. al., (1996): JAMA 276 (24), 1957-1963 Design: multicentre, randomised, double-blind, placebo-controlled Probands: 1,312 Test centres: USA, low selenium regions 1983 - 1996 Period of surveillance: 4.5 years Medication: 200 µg selenium/day

45. Selenium has a tumour-preventive property Results of the Clark-study Reduced incidence for secondary carcinoma in skin cancer patients by selenium supplementation

46. and cancer Kinds of cancer

47. Cancer figures in Germany Estimated number of cancer incidences in Germany 2002 Man Woman 18,850 11,200 5,500 7,800 6,050 900 oral cavity and throat Hodgkin‘s disease urinary bladder pancreas leukemia stomach 7,100 2,600 6,600 4,750 8,250 850 55,150 mammary gland 11,350 uterine corpus 6,500 cervix 9,950 ovary 32,550 lung 12,450 48,650 prostate 4,350 testes 35,600 large bowel and rectum 35,800 5,850 Non-Hodgkin‘s lymphoma 6,250 218,250* total *Figures without non-melanotic skin cancer 206,000* Source: Gesellschaft der epidemiologischen Krebsregister e.V. in Zusammenarbeit mit dem Robert-Koch-Institut. 5. überarbeitete, aktualisierte Ausgabe Saarbrücken, 2006

48. Prostate carcinoma • important role as chemopreventive agent • correlation between selenium deficiency and increased incidence to contract prostate cancer • inhibition of the growth in vitro by blocking the cell cycle, the DNA synthesis and induction of apoptosis Reduction of prostate carcinoma incidence by preventive selenium administration!

49. Mammary carcinoma • tumour-protective characteristics in vivo • low selenium concentrations in the blood incase of mammary carcinoma patients • secondary lymphedema: - adjuvant therapy with selenium - better transportation of the lymphs - binding of radicals in the congested tissue - positive influence of immunocompetent cells - avoidance of appearance of erysipelas

50. Ovarian carcinoma • second most frequent malignant disease of the female sexual organs • increase with rising age • 9,950 incidences per year • 1.7% risk to contract ovarian carcinomain one‘s life