Section 10: Nutrients and their functions

1. Section 10: Nutrients and their functions • Iron, iodide, mercury 01/20/06

2. Iron • Iron is in Hb, Mb, catalase, cytochromes, peroxidases, ferredoxins, hemes, non-hemes, etc. • Iron is also toxic, especially in its Fe(III) form. • RDA is 10 mg for men and 15 mg for women. There are 3 - 5 grams total in the body. 1

3. Iron As Part of Prosthetic Groups • Depending on the prosthetic group and the protein, iron functions differently. 2

4. Iron Function in Different Hemes • In hemoglobin Fe(II) binds oxygen without oxidation. • In cytochrome oxidase iron accepts and delivers electrons by Fe(II) Fe(III) transitions. 3

5. Uptake of Dietary Iron • Heme is absorbed directly. • Fe(III), along with bicarbonate, binds transferrin and is taken up by receptor mediated endocytosis. • Uptake is retarded by precipitation of Fe(III) as Fe(OH)3. • The components of certain foods bind Fe(III) tightly and the complex is not absorbed, phytates for example. • Solubility is enhanced by lower pH, which reduces the formation of insoluble Fe(OH)2 and Fe(OH)3. • Solubility is enhanced by dietary ascorbate, which reduces Fe(III) to Fe(II) in the stomach and gut. 4

6. Iron Absorption Via Transferrin (Tf) • Tf is secreted into the lumen, it binds 2 Fe(III) & 2 HCO3-. • Tf (Fe)2 binds a receptor in a clatherin coated pit and enters the cell by receptor-mediated endocytosis. • Inside cell, fusion with an acidic endosome frees the Fe(III) from the Tf. • The receptor and Tf are recycled. 5

7. Iron Transport in Blood • In the blood Fe(III) binds a different Tf for transport. • Ceruloplasmin catalyzes Fe(II) = Fe(III). • It appears that membranes transport by translocase requires Fe(II). 6

8. Iron Storage • Inside liver, spleen, mucosal and other cells, Fe(III) is stored as a complex with apoferritin, OH- and Pi. There are ~4000 Fe(III) in a cavity in the ferritin complex. • Apoferritin has 24 subunits (21,000 and 19,000 D) 7

9. Some Iron Reactions ascorbate + Fe(III)  dehydroascorbate + Fe(II) (nonenzymic) Absorbed as heme or as Fe(III)2-transferrin complex Ceruloplasmin catalyzes Fe(II)  Fe(III) + e- ferritin apoferritin + many Fe(III), OH- and Pi Transported in blood as Fe(III)-transferrin complex (structure) 8

10. Iodine • The RDA for iodine (primarily in form of iodide, I-) is 0.15 mg. There are 13 - 23 mg total in the body, almost all in the thyroid. • Uptake from the gut is by diffusion along with other small anions. I- is actively pumped into the thyroid. • Iodide is used to synthesize the hormones thyroxine and triiodothyronine, T3. 9

11. Iodine Deficiency and Toxicity • Deficiency can cause a range of diseases: cretinism, mental retardation, severe goiter, slight enlargement of thyroid gland. • Iodine deficiency is rare in the United States, because of iodinized salt, but is common in much of the world. • Acute toxicity is well-studied in animals: 200-500 mg/kg per day causes death. Chronic toxicity in humans is rare but occurs. Up to 2 mg per day has no adverse effects on healthy adult humans. 10

12. Thyroxine Synthesis • Iodide is used to modify tyrosines of the protein TG, converting it to ITG. • When ITG is proteolyzed, thyroxine and T3 are among the amino acids produced. 11

13. Iodothyroglobulin • When ITG is hydrolyzed the above modified amino acids are produced along with the usual ones. 12

14. Transfer reaction • An alanyl remains when a transfer occurs. 13

15. Iodide Uptake and Thyroxine Secretion • Thyroid stimulating hormone TSH (also called "thyrotropin") is secreted from the pituitary, which in turn is stimulated by thyroid releasing hormone from the hypothalamus. • The binding of TSH to a thyroid cell stimulates I-uptake, ITG synthesis, the proteolysis of ITG to produce thyroxine, and the secretion of thyroxine. • ITG is stored as a colloid in a cavity in the center of the follicle. 14

16. Thyroxine Mechanism of Action • Thyroxine and T3 bind cell receptors and are transferred actively into target cells. • Thyroxine is converted into T3. • T3 binds to nuclear hormone receptors (as do some steroid hormones), which regulates the expression of certain genes. (see S03L0419-21) • This increases the level of resting energy expenditure (basal metabolic rate). • It also contributes to regulating growth and development. • T3 is inactivated by deiodination. 15

17. Thyroxine - Related Therapies • Too little thyroxine production can be treated by administration of iodide or, if that fails, thyroxine. • Too much thyroxine production can be treated by surgery to remove thyroid tissue, or by administration of radioactive iodide to destroy thyroid tissue selectively. 16

18. Mercury Risks • Mercury, in its elemental Hg(0) or its ionic Hg(I) and Hg(II) forms, is toxic. High levels and/or chronic exposure are especially hazardous. • Organomercurics are highly toxic, especially CH3Hg+ (recall the Minamata, Japan disaster). • Hg(0) to CH3Hg+ is a biological, although not human, methylation requiring vitamin B12. • Hg(0) is volatile. • Amalgams are 64+% Hg(0). • It would be irresponsible not to be concerned about Hg safety for patients, and for dental personnel. 17

19. Mercury Exposure Maximum allowable (WHO) 42 mg/day Normal exposure from food, air & water 25-30 Exposure from 12 occlusal surfaces 2-3 Exposure from < 4 occlusal surfaces 0.5 from JODA Spring 1990 • This looks safe. The dental contribution is minor. • What could change to make it look unsafe? Data from another source.(WHO, 1991) Daily Exposure Form of Mercury Dental amalgam 3.0-17.0 µg/day Hg vaporFish and Seafood 0.3 µg/day methylmercuryOther food 0.3 µg/day inorganic HgAir & Water Negligible traces  18

20. A More Recent Study, on Military Personnel“Mercury concentrations in urine and whole blood associated with amalgam exposure in a US military population”Kingman A, Albertini T, Brown LJ. (1998 ) J Dent Res 77(3):461-71 • Significant correlations were detected between amalgam exposure and the total (r = 0.34, p < 0.001) and inorganic 0.34 (r = 0.34, p < 0.001) urinary mercury concentrations on the original scale. Stronger correlations were found for creatinine-corrected total (r = 0.43, p < 0.001) and inorganic (r = 0.43, p < 0.001) urine concentrations. • Based on these cross-sectional data, it is estimated that, on average, each ten-surface increase in amalgam exposure is associated with an increase of 1 mg/L mercury in urine concentration. • (~1 gm creatinine/L urine, so ~1 mg Mg/gm creatinine)

21. Hg Excretion Levels and Symptoms 500-1000 Pronounced symptoms: kidney failure, swollen gums, tremors, nervous system disturbances. 100-500 Mild symptoms: irritability, depression, memory loss, minor tremors, early signs of kidney dysfunction. 25-100 Subtle changes on some tests, but no overt symptoms: decreased response on tests of nerve conduction, brain wave activity and verbal skills. 0-25 No known health effects (currently). (from Consumer Reports, 1991) • Values are µg Hg/g creatinine/day in urine. • The upper limit to urinary mercury attributed to extensive amalgam fillings is 4 on this scale (average person 3-4). • Dental personnel excrete 12-15 µg Hg/gm creatinine/day. 19

22. Creatinine • See S08L01 20

23. A Few Recent Articles on Hg Toxicity • 1. “Dental amalgam and human health.” (2003) Int Dent J. 53:464-8 by Yip HK, Li DK, Yau DC. • 2. “The release of mercury from dental amalgam and potential neurotoxicological effects.” (2002) J. Dent. 30: 243-50 by Sweeney M, Creanor SL, Smith RA, Foye RH. • 3. “Dental workplace exposure and effect on fertility.” (1999) Scand J Work Environ Health 25:285-90 by Dahl JE, Sundby J, Hensten-Pettersen A, Jacobsen N, • 4. “Mercury exposure due to environmental factors and amalgam restorations in a sample of North Carolina children”. (1999) Pediatr Dent 21:114-7 by Dilley DC, Bawden JW You may wish to look at these articles. 21

24. Web links Transferrin structure. Almalgam mercury information CDA ADA Next topic: Vitamin A