1. Phar 722 Pharmacy Practice III Trace Elements- Zinc Spring 2006

2. Zinc Learning Objectives Know the uptake, distribution and excretion of zinc. Know the bioavailability of dietary zinc. Know the biodistribution of zinc. Know the biochemical functions of zinc. Know the causes and symptoms of zinc deficiency. Know the symptoms of zinc toxicity. Know the current efficacy of zinc supplements in certain diseases discussed in class. List the common side effects of oral zinc therapy. Know the RDAs for adults and ULs for children and adults.

3. Zinc’s Three Biochemical Roles-1 Catalytic Role Structural Role Regulatory Role

4. Zinc’s Three Biochemical Roles-2 Catalytic Role –Over 100 specific zinc metalloenzymes depend on zinc for catalytic activity including: Alcohol dehydrogenase Ribonucleic acid polymerases Carbonic anhydrase Alkaline phosphatase Carboxypeptidase Glutamic dehydrogenase Lactic dehydrogenase –Mechanism Zinc is a Lewis acid accepting electrons (different from oxidation-reduction reactions)

5. Zinc’s Three Biochemical Roles-3 Structural Role –Coordinates with electron rich amino acid side chains of proteins stabilizing tertiary and quaternary structure. Copper-zinc superoxide dismutase –Copper is the cofactor in the oxidation-reduction reaction and zinc stabilizes tertiary structure. –Intracelluar binding of tyr kinase to T-cell receptors. –Coordination with cys and his residues produces “zinc finger-like” structure. Zinc fingers are important regulators of DNA binding transcription factors.

6. Zinc’s Three Biochemical Roles-4 Regulatory Role –This function is poorly understood. Examples include: Regulator of gene expression possibly by changes in binding to transcription factors. Zinc transporter proteins –Metallothionein gene producing a metalloprotein that regulates zinc trafficking. Apoptosis Protein kinase C activity –Cell signaling

7. Uptake, Utilization & Excretion-1 Dietary zinc is bound in metalloproteins (see previous slides). The digestive process frees it –It then becomes bound to endogenous proteins found in the intestinal lumen. There is active transport in the jejunum. –Zinc transport speeds up in states of zinc depletion. The human body contains about 2 gm zinc. –Over 85% of these 2 gm is in skeletal muscle and bone. –0.1% of total zinc (10 – 15 μmol/L) in plasma.

8. Uptake, Utilization & Excretion-2 Zinc apparently uses the same transport systems as other divalent cations. –Iron supplements might lower the percent of zinc absorbed. –Zinc supplements might lower the percent of copper absorbed. Zinc elimination is by secretion into the intestine followed by excretion in the feces.

9. Zinc Deficiency Symptoms do not correlate with zinc’s biochemical roles. –Depressed growth –Delayed sexual maturation –Immune dysfunction –Diarrhea –Altered cognition –Defects in carbohydrate utilization Causes –Intestinal disease Sprue, Crohn’s Disease, short bowel syndrome –Eating grains high in phytic acid (inositol hexaphosphate) May be an important consideration for strict vegetarians who concentrate on grains. NOTE: There is no agreed-upon clinical test for zinc status.

10. Zinc’s Possible Role in Treatment of Disease-1 “Common” Cold –The results of zinc lozenges are mixed. –There is risk of overdosing if these lozenges are used for prolonged periods (6-8 weeks). –Zinc is an astringent and may irritate the mound and GI tract. Age-related macular degeneration. –Three is no evidence that zinc either causes or reduces the risk of this disease. –There are ongoing trials of anti-oxidant vitamins and selenium. Diabetes mellitus –Zinc does affect glucose metabolism. –Patients with diabetes taking zinc supplements should carefully monitor their blood-glucose levels.

11. Age-Related Macular Degeneration

12. Zinc’s Possible Role in Treatment of Disease-2 Wound healing –This claim has been made for nearly 40 years. –There have been recommendations that zinc supplements hastens healing of bed sores and other forms of skin ulcerations. Immune system –Zinc is required for a proper immune response. –There is some evidence that HIV/AIDS patients may benefit from zinc supplements. For these studies, it is important to check on the nutritional status of HIV/AIDS patients. –Otherwise, the results are mixed that zinc facilitates the immune response.

13. Zinc Toxicities Zinc is a potent astringent. Acute Symptoms –Many of the symptoms probably caused by zinc’s astringent properties. Epigastric pain Nausea Vomiting Abdominal cramps Diarrhea Chronic Symptoms –Zinc competes with other metals at the transport sites. Suppression of immune response Decrease in HDL Decrease in copper levels

14. Dosages Forms Zinc acetate Zinc gluconate Zinc picolinate –No evidence that the zinc in this salt is more bioavailable. Zinc sulfate Zinc oxide

15. Dietary Reference Intakes-1 AI –Infants (0-6 months)2.0 mg/day EAR –Infants (7-12 months)2.5 mg/day –Children (1-3 years)2.5 mg/day –Children (4-8 years)4 mg/day –Children (9-13 years)7 mg/day –Boys (14-18 years)8.5 mg/day –Girls (14-18 years)7.3 mg/day –Men (19-70+ years)9.4 mg/day –Women (19-70+ years)6.8 mg/day –Pregnancy (14-18 years)10.0 mg/day –Pregnancy (19-50 years)9.5 mg/day –Lactation (14-18 years)10.9 mg/day –Lactation (19-50 years)10.4 mg/day

16. Dietary Reference Intakes-2 RDA –Infants (7-12 months)3 mg/day –Children (1-3 years)3 mg/day –Children (4-8 years)5 mg/day –Children (9-13 years)8 mg/day –Boys (14-18 years)11 mg/day –Girls (14-18 years)9 mg/day –Men (19-70+ years)11 mg/day –Women (19-10+ years)8 mg/day –Pregnancy (14-18 years)12 mg/day –Pregnancy (19-50 years)11 mg/day –Lactation (14-18 years)13 mg/day –Lactation (19-50 years)12 mg/day

17. Dietary Reference Intakes-3 UL –Infants (0-6 months)4 mg/day –Infants (7-12 months)5 mg/day –Children (1-3 years)7 mg/day –Children (4-8 years)12 mg/day –Children (9-13 years)23mg/day –Boys (14-18 years)34 mg/day –Girls (14-18 years)34 mg/day –Men (19-70+ years)40 mg/day –Women (19-70+ years)40 mg/day –Pregnancy (14-18 years)34 mg/day –Pregnancy (19-50 years)40 mg/day –Lactation (14-18 years)34 mg/day –Lactation (19-50 years)40 mg/day

18. Dietary Sources Shellfish Beef and other red meats Nuts and legumes The zinc in leavened whole grain breads is more bioavailable. –Yeast consumes some of the phytic acid.