Zinc Flashcards
What is free-radical theory of aging?
aging process due to cumulative oxidative damage to cells
- minimizing reactive oxygen species/free radials may be “key” to anti-aging
What is the role of oxidative stress play in multiple chronic diseases?
Atherosclerosis -> blood clots or heart attacks
Cancer
Cataracts -> Impacts vision
Autoimmune diseases
Lung damage
What is oxidative stress?
Reactive oxygen species and other reactive species oxidize (=”steal electrons from”) DNA, proteins, lipids
Unpaired electrons on the “hunt” for an electron for this pairing => Free radical
What is oxidation?
Chemical reactions that produce free radicals, leading to chain reactions that may cause damage to cells and tissues
What are some reactive species?
- Highly reactive, oxygen-containing molecules
e.g., superoxide radical (O2-), hydroxyl radical (OH), hydrogen peroxide (H2O2) - Reactive nitrogen species: e.g., Ntirtic Oxide (NO)
- Other reactive species:
e.g., Thiyl RS, Trichloromethyl (CCl3)
How are reactive species generated?
- Exposure to exogenous substances
- chemicals in the environment (pollutants)
- smoking
- drugs
- radiation - Physiological processes
- Enzymatic reactions, oxidases
- Electron transport chain
- Immune defence (superoxide = antimicrobial)
What are the consequences of cellular oxidative damage?
Lipids (PUFA) - lipid peroxidation: loss of membrane fluidity, receptor functions and potentially cellular lysis
Protein degradation - cross-linking; inactivation; denaturation
Carbohydrates - altered glycoprotein function (hormonal and neurotransmitter receptors, cell recognition)
Nucleic acids - DNA damage; mutations; carcinogenesis
What is an antioxidant?
molecules that inhibit the oxidation of other molecules
protectors to oxidative stress
donor of electron to free radical but does not become one
What are some antioxidants?
Enzymes:
1. Catalase (contains 4 heme groups): catalyzes the decomposition of hydrogen peroxide to water and oxygen
2 H2O2 -> 2 H2O + O2
- Cu/Zn superoxide dismutase (SOD) - both oxidization and reduction
Cu2+-SOD + O2- -> Cu+-SOD + O2 = reduction of copper and oxidation of superoxide
Cu+-SOD + O2- + 2H+ -> Cu2+-SOD + H2O2 = oxidation of copper and reduction of superoxide
Micronutrients: vitamin C, vitamin E, beta-carotene
What is the most occurred form of zinc in our body?
Zn2+ can essential micromineral or trace element
What are the metabolic functions of zinc?
- Component of metalloenzymes (>300)
- Gene expression - Zinc fingers -> gene transcription
- Membrane stabilization
- Insulin response and glucose tolerance
- Immune function - development and differentiation of immune cells
- Sexual maturation - fertility, reproduction and development
What are the >300 metalloenzymes?
Provides structural integrity to the enzymes and participates in reaction at the catalytic site
Ex. zinc functions through cofactor role in metalloenzymes
A. Antioxidant function through role in Cu/Zn superoxide dismutase
B. Synthesis of proteins, carbohydrates, lipids, DNA and RNA (cofactor enzymes such as kinase, phosphorylases, etc.,)
C. Digestion of nutrients
D. Synthesis of heme
E. Wound healing
D. Acid/base balance (carbonic anhydrase) - blood bicarbonate (HCO3-) = buffering agent to control blood pH
How is zinc involved in gene expression?
- important for gene expression and regulation
- Zinc fingers -> structural role in regulating gene transcription e.g., estrogen receptor; glucocorticoid receptor
What are natural food sources of zinc?
Predominantly in meats and seafood
Plant sources have less zinc and zinc is less well absorbed from plant sources
Supplements are zinc salts
How is Zinc digested?
- hydrolysis of zinc from amino acids and nucleic acid before absorption
- zinc release by HCl in the stomach, and by proteases and nucleases in the stomach and small intestine
How is Zinc absorbed?
Where: small intestine, mainly in the duodenum and upper jejunum
How:
Carrier mediated through ZIP-4 = major transporter of zinc across the brush border
- ZIP-4 degraded with higher Zn intakes = mechanism for maintaining Zn homeostasis
Minor pathways: DMT1 (iron and calcium) and bound to amino acids via amino acid transporter
Paracellular diffusion - between the cells at high intakes (>20 mg)
What is the overall absorption rate affect the bioavailability?
Overall absorption rate - influenced by zinc status, zinc intake, and enhancer/inhibitors
- 20-50% of ingested zinc is absorbed
How does zinc intake affect the bioavailability?
100% absorbed at intake level < 1 mg
30-40% absorbed at an intake level of about 12 mg
Less absorption with higher intakes
What enhances zinc bioavailability?
Amino acids, and organic acids - form soluble complexes with zinc
Higher acidity
What inhibits zinc bioavailability?
Phytic acid, oxalic acid, polyphenols - form complexes with zinc that are not absorbed
Non-heme iron (particularly at high doses)
How is Zinc transported from enterocytes?
3 possible fates of absorbed zinc:
1. Used intracellularly for biochemical functions
2. Stored or sequestered in vesicles, endosomes, or Golgi networks
3. transported through the cytosol bound to proteins, and across the basolateral membrane
Zinc transporter passage through the basolateral membrane -> ZnT1
How is zinc transported in the blood?
Plasma - Bound forms
- albumin (main) -> transport protein
- other proteins
- amino acids, e.g., histidine and cysteine
Little zinc is found free
How is transported Zinc uptaken in the tissue?
transporters - ZIPs as importers; also DMT1
Zinc transporter (ZnTs) as exporters
Within cells: Zinc bound to proteins in the nucleus (30-40%), cytosol (50%), cell membrane (10%)
How is zinc stored?
Bound to metallothionein
- considered storage complex
- metallothionein synthesis stimulated by zinc
total body zinc = 1.5 - 3.0 g mostly in the liver, kidneys, muscle, skin, bones
What are the functions of metallothionein?
Intracellular transport of zinc
Detoxifying heavy metals
Stabilizing membranes
Antioxidant
How is zinc excreted?
Fecal excretion (main):
Unabsorbed zinc
Desquamated intestinal cells -> cells being replaced/recycled
Endogenous zinc
- from metalloproteins (e.g., digestive enzymes) secreted from the pancreas etc.; some may be re-absorbed
- purposeful intestinal excretion of zinc by ZIP5 -> facilitates zinc transport from blood across the basolateral membrane into enterocyte, through brush border membrane by ZnT6 into the lumen; 3 mg/d losses, fecal losses increase with increasing zinc intake -> Zinc homeostasis
Urinary losses (minor)
Sweat, hair, & skin loss (minor)
What is the nutrient-nutrient interaction between zinc and iron?
Interference
- zinc and iron are absorbed by DMT1 in the intestine; combined supplementation leads to a lower increase in iron status compared to iron supplements alone
What is the nutrient-nutrient interaction between copper and zinc?
Zinc stimulates synthesis of metallothionein which has higher affinity for copper than zinc - copper bound to metallothionein in enterocyte becomes “trapped” -> zinc-induced copper deficiency possible
What is the nutrient-nutrient interaction between vitamin A and zinc?
Zinc is required for alcohol dehydrogenase structure and activity; retinol is converted to retinal by alcohol dehydrogenase; critical step in function of vitamin A
Zinc needed in hepatic synthesis of retinol-bindin protein that transports vitamin A in the blood; decreases vitamin A mobilization in case of zinc deficiency
What are the health implications caused by zinc deficiency?
Children:
- growth retardation (stunting)
- skeletal abnormalities
- delayed sexual maturation
Adults:
- anorexia
- lethargy
- depression
- blunting of sense of taste
- some hair loss
- vision problems
- impaired immune function
Symptoms: Diarrhea, Poor wound healing, skin rash/lesions/dermatitis
Who are at risk for zinc deficiency?
- Inadequate intake: low/no intake of animal-source foods
e.g., vegetarian diet, low socioeconomic status - Older adults - reduced gastric acidity, often poorer nutrition
- Alcohol consumption - reduced intestinal zinc absorption and increased urinary zinc excretion
- Diuretics and other medications - enhance zinc excretion as they stimulate urinary excretion and zinc reabsorption is not regulated
- Diseases/conditions that cause malabsorption
- Crohn’s disease
- short bowel syndrome
- celiac disease - Other disease
- liver failure
- surgical bariatric procedures
- diarrhea
What are risk factors?
- Digestive disorders (e.g., chronic diarrhea) and other diseases (e.g., sickle cell disease)
- Malnutrition
- Vegetarian diet
- Older babies who are exclusively breastfed
What is the tolerable upper intake level of zinc?
40 mg/day
What are acute toxicity of excess zinc?
- vomiting
- abdominal cramps
- GI distress
What are chronic toxicity of excess zinc?
- suppression of the immune system
- copper deficiency - impairs copper balance
- anemia
