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1pp HUN 4221 Selenium 11 - • Quiz 7 Th Copper Zinc...

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Unformatted text preview: • Quiz 7 Th Copper, Zinc, Selenium • Th Lecture: Electrolytes • Tues Lecture: Iodine • Extra point question in class on video about creatinism- link emailed Selenium Selenium 2011 Selenium Selenium History • 1957 Schwarz and Foltz – dietary Se prevents liver necrosis in rats fed fed Se deficient diet also deficient in Vit E Selenium History • Proof that Se essential for animals • Widespread use of Se animal feeds – eliminated animal diseases • due to Se deficiency Selenium Selenium History • 1960-1970’s Research – Se has anticarcinogenic activity • Discovery of glutathione peroxidase – Se metalloenzyme Selenium: Selenium: Dietary Sources • Good sources: Good – fish, seafood, eggs, meat, vegetables • Foods vary depending on – where plant is grown – where animal raised • Se content of meat reflects – Se in diet supplements – livestock in US supplemented with inorganic Se Selenium Selenium Distribution in the US Types Types of Selenium • Inorganic and organic Inorganic forms, and both are present present in the body. Inorganic •Selenite (SeO32-) Organic •Selenate (SeO42-) •Selenocysteine (Sec) •Selenide (HSe-) •Selenomethionine Absorption Absorption • Selenomethionine- and selenocysteinecontaining proteins: – Selenoamino acids absorbed intact by animals and humans As – As high as 98% • Inorganic Se forms: – Absorption ~85% Fig. 12-15, p. 507 Intestinal Intestinal Transport • Luminal and basolateral inorganic Se Luminal transporters: – None have been described, different from different other minerals. • Selenomethionine and methionine transported the same. • Se absorption rate does not increase in deficiency. (Liuzzi et al., PNAS 2004) Body Body Composition • Total body Se ≈ 30 mg • Tissues: – Kidney greatest Se concentration 0.6-1.8 μg/g – Others liver > RBCs > muscle > spleen > pancreas – Muscle = largest Se mass Blood Blood Levels and Excretion • Blood levels in the U.S. population – 125 μg/ L • China = 15 μg/ L • Excretion: – Methylselenol: major urinary form – Urinary excretion important for maintaining homeostasis (i.e., urinary Se decreases when in limited supply) Fig. 12-16, p. 508 Metabolism Metabolism • Catabolism of selenomethionine or Catabolism selenocysteine releases inorganic Selenide (HSe-). • SeO2- and SeO3- also reduced to SeO selenide (HSe- ) • Selenide (HSe- ), after enzymatic conversion to Selenocysteine (Sec), is then utilized for biosynthesis of bi selenoproteins. Overview Overview of Se Metabolism (Adapted from Sunde, R.A. (1997) Selenium. I n: Handbook of Nutritionally Essential Mineral Elements , p. 493). Functions Functions of Selenoproteins • The functions of most selenoproteins The are unknown. • However, the selenoproteins that have been characterized participate in antioxidant and anabolic processes Glutathione Glutathione Peroxidase 1 • Discovered in 1957 Discovered by Mills. • The first selenoprotein identified. • Accounts for > 50% of total body Se. Classical Classical Glutathione Peroxidase (GPX) • H2O2 is reduced by the activity of GPX utilizing GSH. • The selenocysteine component of GPX is necessary for enzymatic activity. • Additionally may function as a biological Se buffer. Selenium Selenium and Glutathione Peroxidase 1 GPX1 • Key Points: – GPX1 accounts for > 50% of total body Se, and and may function as a Se-buffer. • May be broken down to provide Se for other functions – Selenocysteine is a key component of GPX1. Other Other Glutathione Peroxidases GPXs • GPX3 – Plasma GPX – Major form of Se in milk • GPX4 – Structural component of sperm– Se deficiency can lead to male infertility Iodothyronine Iodothyronine Deiodinases • Family of 3 Family selenoenzymes • Thyroxine 5’deiodinase (DI1) – Present in the liver – Responsible for the conversion of T4 to T3 * Se deficiency ↓ DI1 activity, however compensation occurs. (Larsen, P.R., and Berry M.J. (1995) Annu Rev Nutr; 15:323) Thioredoxin Thioredoxin Reductases (TRRs) • Family of 3 SE-containing enzymes – Thioredoxin Reductases May regulate intracellular redox state. – Enzymes facilitate transfer of electrons from NADPH to thioredoxin, leading to its its reduction. • Thioredoxins are small proteins in cells that act as antioxidants by donating hydrogens to oxidized oxidized compounds – Thioredoxin Reductases (TRRs) will reduce dehydroascorbate, ascorbate radical, and possibly regenerate Vit. E (Sun et al. (1999) JBC; 274:24522) SelenoproteinW SelenoproteinW (SELW) • Small selenoprotein Small found in muscle (cardiac and skeletal) – Implicated in white muscle disease – Decreased in Se deficiency leading to muscle weakness • Prevention: – Supplement soil with Se Selenoprotein Selenoprotein P (SELP) • Major plasma selenoprotein – Accounts for 80% of plasma Se – Major Se transport protein • Produced by the liver • Up to 10 Se atoms/ molecule – May function as an antioxidant Se Se Deficiency Se-Def e- • Se has been shown to correct liver necrosis caused by lack of methionine, cystine, or vitamin E. • Se deficient rat: visually smaller leg smaller, leg weakness, and and rough hair coat. • Upon examination: animals display muscle degeneration, reproductive failure and liver necrosis if also also Vit. E deficient. deficient Test Test Question • Your research protocol includes Your providing a selenium-free diet to laboratory animals. You expect to You observe: (a) Increased glutathione peroxidase activity (b) Increased requirement for Vitamin E Vit (c) Decreased tissue concentration of H2O2 (d) (d) Increased Serum T3 Test Test Question • Your research protocol includes Your providing a selenium-free diet to laboratory animals. You expect to You observe: (a) Increased glutathione peroxidase activity (b) Increased requirement for Vitamin E Vit (c) Decreased tissue concentration of H2O2 (d) (d) Increased Serum T3 Human Human Se Deficiency • Keshan Disease Causes cardiomyopathy – 2 main factors Implicated in dz etiology: • – • Low levels of Se in certain areas Viral Infection Keshan disease has nearly been eradicated due to Se supplementation. Keshan SKIP SKIP Human Se Deficiency • Kashin-Beck disease – Currently affects ~ 8 million people in regions of Northern China and Russia where soil Se is low. – Endemic dz of the cartilage – Se supplementation does not cure dz. – Iodine deficiency may be involved. Human Human Se Deficiency • Myxedematous Cretinism – Disease characterized by thyroid enlargement enlargement and decreased intelligence. – Se & Iodine deficiency contribute to etiology. etiology. – Watch video about cretinism before next Watch Tuesday –link to video emailed Selenium: Selenium: Status Assessment • Intake indicators – plasma/serum selenium • Reflects recent diet – red blood cell selenium • Past 120 days Selenium: Selenium: Status Assessment • Functional indicator – glutathione peroxidase activity Test Test Question The The functional indicator of selenium status is measurement of seleniumdependent catalase activity. • True • False Test Test Question The The functional indicator of selenium status is measurement of seleniumdependent catalase activity. • True • False Selenium Selenium RDA • Men and Women 55 μg/day • Pregnancy 59 μg/day • Lactation 70 μg/day 70 /d • Upper Limit 400 μg/day Se Se Toxicity • Toxicity first identified in livestock. – Consumed plants grown in high-Se soil • In rats, there is only a factor of 20 there difference between adequate and toxic levels levels of Se. • Inorganic Se and amino acid forms are highly bioavailable, thus toxic in excess. bi Se Se Toxicity • Selenosis (Chronic Se Toxicity) – Commonly associated with: • Changes in nail structure, loss of nails, and hair – Continued ingestion leads to: • Lesions of the skin and nervous system • Nausea • Weakness • Diarrhea – Symptoms present with intake range of 3.2-6.7 mg/ day. • Acute Se Toxicity – Caused by ingestion of gram quantities of Se • GI and neurological disturbances • MI (Myocardial infarction) • Renal failure • Acute respiratory distress syndrome No antidote for overdose. Se Se and Cancer • Clark, L.C. et al (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA; 276: 1957. 276 1957 • Controlled Intervention Trial – 200 μg Se/ day • No effect of Se on the primary endpoint (Squamous cell carcinoma) • However, Se ↓ lung, prostate, and colon cancer incidence compared to the lowest Se intake group. Effect of Se and Vitamin E on Risk of Prostate Cancer • SELECT – The Selenium and Vitamin E Cancer Prevention Trial • Randomized, placebo-controlled trial • Mean = 5.46 years; n = 35,533 men • Interventions: – – – – Selenium (200 μg/day) + vitamin E placebo Vitamin E (400 IU/day) + selenium placebo Selenium + vitamin E Placebo + placebo • Primary outcome measure: prostate cancer Lippman et al. (2009) JAMA 301(1):39-51 Results Results • No sig increase in No prostate cancer in selenium + vitamin E or selenium group • Trend for increase in prostate cancer in vitamin E group (p=0.06) Conclusions Conclusions • Selenium or vitamin E, alone or in Selenium alone combination, did not prevent prostate cancer cancer in these men. • Note: SELECT study stopped early in October 2008 because data showed supplements do not prevent prostate cancer ...
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