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History
1509, recognized as element
Essentiality demonstrated
Plants: 1869
Animals: 1934
Deficiency
Considered unlikely until 1955
swine parakeratosis shown to be caused by Zn deficiency
conditioned human deficiency demonstrated in 1956
Zn++ Zn++
Saturable =
Bound to CRIP-Zn Albumin
form transport MTI-Zn
ligand Zn++-Albumin
MTI
Zn++ Zn++
Non-saturable = Passive Diffusion
hZIP3
Number of transporters
DCT1: duodenum, jejunum, kidney, bone
marrow, others
Non-specific: Zn, Cd, Mn & Cu actually have slightly
higher affinity than Fe, the mineral for which the
transport actions of this protein was first identified.
Competition between Fe & Zn & Cu
Storage
Storage sites
No specfic storage sites are recognized
Within cells, amounts sequestered within metallothionine
could be considered as stores
Anorexia, muscle catabolism, tissue zinc release
Metalloenzymes cling tenaciously to zinc
Serum/plasma zinc drops rapidly (~1 week) with zinc
deficient diet
Zinc turnover is extensive and rapid
Two-components of turnover, fast ~12.3 days, and slow, ~300 days
Fast pool is also called the “exchangeable” pool
Usually amounts to 157-183 mg Zn
Excretion
Lost via hair, sweat, desquamation, bile pancreatic secretions,
seminal fluid, urine, feces
Main endogenous loss
Secretions into gut
Bile and pancreas
Mucosal cells
Urinary and integumental losses
< 20% under normal conditions
Losses increase with trauma, muscle catabolism, and administration of chelating
agents (EDTA)
Primarily in fecal material
Unabsorbed Zn
Secreted Zn (endogenous sources)
From pancreatic and intestinal sources
Regulation
Metallothionein
Concentrated in liver, kidney, pancreas, intestine
Acts as a Zn2+ buffer
Controls free Zn2+ level
Control intracellular Zn pool responsive to both hormones and diet
Zn-binding protein, metallothionein (MT), is involved in the
regulation of Zn metabolism
MT is inducible by dietary Zn via the metal response element
(MRE) and MTF-1 mechanism of transcriptional regulation
↑ in cellular MT ↑ Zn binding within cells
Acute infections associated with proinflammatory cytokines
increses Zn uptake into liver, bone marrow and thymus and
reduces the amount going to bone, skin and intestine
Metabolic Interactions
Interactions of other divalent cations in the
intestinal lumen
Fe, Sn, Cd → ↓ Zn
↑ Zn → ↓ Cu
Interactions
Copper
High Zn diets reduce Cu absorption
electronic configuration competition
Metallothionine synthesis induced
sequesters Cu in mucosal cell preventing serosal
transfer
Happens with 150mg Zn for two years
Can be used with Wilson’s disease patients
High copper diets do not interfere with Zinc absorption
Iron
Supplements inhibit zinc absorption
Ferrous > Ferric, heme no effect
Pregnant and taking >60mg Fe/day should also take
Zn
Interactions
Calcium
High Ca diets reduce Zn absorption
effect enhanced in phytate rich diets
not sure how much of a problem in humans
post menopausal women yes, adolescent girls, no
Other
Tin (Sb), not usually high in diet, but diets high in
Tin can increase fecal Zn excretion
Cadmium (Cd), alter Zn distribution in body
rather than altering absorption
Folic acid, conjugase requires Zn
High doses sometimes impair Zn status further in low
Zn situation - mechanism currently unclear
Function
Zinc-containing enzymes
More than 70 enzymes
Secondary & tertiary protein structures
Metal stabilized active sites
Examples of general types
dehydrogenases
phosphatases
peptidases
kinases
deaminases
Insulin
Function
Zinc-Finger
Function
Zinc-finger
Interacting with DNA
Function
Zinc Fingers
Mutation c/ablation of binding
in case of Zif268, loss in sequence-specific DNA
binding that allowed viral infection
Iron can replace Zn in “fingers”
Low Zn and high Fe
Fe gives rise to ROS more readily
DNA damage & carcinogenesis?
Cadmium can replace Zn in “fingers”
Non-functional, cytotoxic
Transcription Factors
Revelation
Gene expression is controlled by specific proteins
call transcription factors
Zinc containing transcription factors account for 1%
of genome
Zinc plays key structural role in transcription
factor proteins
Ligands for transcription factors include:
Vitamin A
Vitamin D
Bile acids
Thyroid hormones
Membrane Stability
Membrane fractions contain high concentrations
of Zn
Increases rigidity of cell
Protection from oxidative damage
Competition for binding sites with redox metals
Membrane Function
In deficient animals:
Failure of platelet aggregation
Due to impaired Calcium uptake
Peripheral neuropathy
Brain synaptic vesicles exhibit impaired calcium uptake
Increased osmotic fragility in RBCs
Decreased plasma membrane sulfhydryl concentration
Immune Function
After Zinc depletion
All functions within monocytes were impaired
Cytotoxicity decreased in Natural Killer Cells
11-cis-Retinol trans-Retinol
Zn and Vitamin A Interaction
Mechanisms of Toxicity
Excess accumulation within cells may disrupt
functions of biological molecules
Protein, enzymes, DNA
Leads to toxic consequences
Anemia
Impaired copper availability
Acute excessive intakes
Local irritant to tissues and membranes
GI distress, nausea, vomiting, abdominal cramps, diarrhea
Relatively non-toxic
Sources of exposure – drinking water, feed, polluted air
Deficiency
Signs More signs
Growth retardation
Night blindness
Delayed sexual maturation &
impotence Impaired taste (hypoguesia)
Impaired testicular development Delayed healing of wounds,
Hypogonadism & hypospermia burns, decubitus ulcers
Alopecia Impaired appetite & food
Acroorifical skin lesions intake
Other, glossitis, alopecia & nail Eye lesions including
dystrophy photophobia & lack of dark
Immune deficiencies adaptation
Behavioral changes
Deficiency
Monogastric more susceptible
Chickens & pigs used to become deficient with high corn
diets
Old enemy phytate
Ruminants resistant due to ability to break down phytates
Diabetes
Increases urinary zinc excretion
Can cause deficiency
Elderly
Poor intakes & altered physiology
Deficiency During Pregnancy
Zn deficient rats failed to conceive
Abnormalities of blastocyst development
Offspring had high incidence of abnormalities
Deformities of brain, skull, limbs, eyes, heart, lungs
Low Zn intake during the third trimester may
not have such profound effects
Main stages of differentiation are already complete
Can result in low birth weight, and prolonged and
difficult parturition
Deficiency During Pregnancy
Zinc
Zinc
Adequate
Deficient
3 days 4 days