Trace Metals

Definition – Trace Metals

micronutrients required in the diet for necessary cellular functions
Major examples
- iron (Fe)
- copper (Cu)
- zinc (Zn)
- chromium (Cr)
- fluoride (F)
- iodide (I)
- selenium (Se)
Others
- V, Mo, Mn, Co, and Ni
Function
- part of metalloenzyme
  - enzyme has no activity without the metal
  - metal is fixed
  - metal:protein is constant
  - example
    - carbonic anhydrase
- part of metal-containing enzyme
  - enzyme may have activity without the metal
  - metal is reversibly bound
  - metal:protein ratio is variable
  - example
    - glycogen phosphorylase kinase
Oxidative stress
- organometallic side reactions that damage tissue
  - many metals undergo the Fenton reaction in vivo
    - oxidation of metal and donation of an electron to oxygen
    - most common metals that undergo reaction are Fe²⁺ and Cu⁺
    - creation of hydroxyl radicals
  - heme iron can generate superoxide radicals (O₂*)
- reactions happen frequently, but the body can defend itself with anti-oxidants
  - oxidative stress occurs when pro-oxidants > anti-oxidants.
- examples of oxidative stress damage
  - stroke
  - Parkinson’s
  - Alzheimer’s

Iron

Source
- diet
- recycled from destroyed erythrocytes
Forms
- ferrous iron (Fe²⁺)
  - dangerous
  - causes oxidative stress
  - found in hemoglobin
- ferric iron (Fe³⁺)
  - less dangerous
  - methemoglobinemia (metHb) occurs when Fe³⁺ is found in hemoglobin
Absorption
- Fe-containing compounds are solubilized in low stomach pH
- Fe³⁺ is reduced to Fe²⁺ (requires vitamin C) in intestine so it can cross gut lumen
- ferroportin brings Fe³⁺ into bloodstream from enterocytes
  - mediates amount of Fe released into the blood
  - hepcidin inhibits ferroportin
    - antibacterial because it lowers the availability of iron in the plasma
Storage
- must be immediately used or stored to prevent:
  - bacterial utilization
    - Fe required for growth
  - formation of iron oxides
  - free radicals (Fe + O₂)
- site
  - hepatocytes (main)
  - enterocytes
  - macrophages
- stored as ferritin (Fe³⁺)
- hemosiderin binds excess Fe³⁺ to prevent from entering the blood
Transport
- carried as Fe³⁺ by transferrin in the blood
  - transferrin chelates the Fe³⁺ and transports it in the blood to tissues.
    - maintains solubility and keeps unreactive
    - transferrin receptors on cells endocytose transferrin:Fe complex
    - Fe³⁺ released into cell triggered by low pH
    - transferrin returns to cell surface to be used again
- ferroxidase (aka ceruloplasmin) oxidizes Fe²⁺ to Fe³⁺ for transport and storage
  - ferritin can also oxidize Fe for storage
Excretion
- no cellular mechanism for iron excretion
- lost from blood loss and removal of skin cells and other epithelial cells
Toxicity
- beyond the sequestration capacity of ferritin
- causes oxidative stress
Disorders in iron handling
- hereditary hemochromacytosis

Copper

Role
- human metabolism
- like other metals, free copper is potentially toxic by donating electrons
  - creates hydroxyl radicals and other reactive oxygen species
- copper is a cofactor for many metalloproteins
  - examples
    - lysyl oxidase (collagen synthesis)
    - tyrosinase (melanin synthesis)
Transport
- albumin and ceruloplasmin carry copper in the blood
  - similar role to transferrin in iron transport
- metallothionein is a carrier of copper, zinc, and many other metals
  - role in preventing oxidative stress in the cell
  - thiol groups from many cysteine residues mediate binding
Excretion
- excess copper removed in the bile
  - unlike iron with no mechanism of excretion
Deficiency
- causes
  - excess zinc
    - metallothionein carries both copper and zinc
    - copper is displaced when zinc concentrations rise
- symptoms
  - a function of what enzymes require copper
    - ferroxidase
      - catalyzes oxidation of iron from Fe²⁺ to Fe³⁺
      - result is microcytic anemia
    - lysyl oxidase
      - crosslinks collagen fibers
      - result is poor wound healing
      - aortic dissection
Disorders in copper handling
- Wilson’s disease
- Menke’s disease
  - X-linked gene mutation in ATP7A
    - ATP-dependent copper efflux protein
  - aka Ehlers-Danlos syndrome type IX
  - inability of enterocytes to release absorbed copper
  - copper at toxic levels in small intestine and kidneys
  - copper in circulation and in brain at low levels
  - symptoms
    - presents like a copper deficiency
    - seizures, failure to thrive, and neurodegeneration
    - steel-colored and brittle hair
      - due to role of copper in metalloprotein lysyl oxidase which crosslinks collagen for added strength
      - at low serum concentrations of copper, this enzyme cannot function

Zinc

Function
- hundreds of enzymes require zinc
  - important examples
    - carbonic anhydrase
    - ACE (angiotensin I converting enzyme)
    - RNA and DNA polymerase
Transport
- metallothionein carries zinc
  - competes with copper
Deficiency
- causes
  - poor diet
  - alcoholism
    - liver unable to handle zinc properly
- symptoms
  - impaired collagenase
    - delayed wound healing
  - impaired zinc finger transcription factor motifs
    - hypogonadism
      - ↓ adult hair (axillary, facial, and pubic)
  - ↓ in senses
    - dysgeusia (lack of taste)
    - anosmia (lack of smell)
  - diarrhea
  - hair loss (alopecia)

Chromium

Deficiency
- causes
  - total parenteral nutrition (TPN)
- symptoms
  - a function of what proteins/enzymes require chromium
    - hypothesized to play a role as part of glucose tolerance factor
      - ↓ glucose tolerance

Flouride

Source
- mainly fluoridated water
Deficiency
- plays a role in bone and teeth formation/strength
  - ↑ bone fractures
  - dental caries

Iodine

Source
- mainly iodized salt
Deficiency
- plays a role in synthesis of thyroid hormone
  - goiter
  - ↓ thyroid hormone output

Selenium

Deficiency
- causes
  - total parenteral nutrition (TPN)
- symptoms
  - plays a role in glutathione peroxidase that protects against oxidative stress
    - damage to tissues with high metabolic activity
      - muscle pain
      - cardiomyopathy

Function

Trace metals, also known as trace elements, are minerals that are required by the body in small amounts but are essential for various physiological functions. These include:

Enzyme activity: Many trace metals are essential components of enzymes, which are proteins that catalyze biochemical reactions in the body. For example, iron is a key component of hemoglobin, which is required for oxygen transport in the blood, and zinc is involved in the activity of over 300 enzymes.
Structural support: Some trace metals, such as copper and zinc, are important for the structure and stability of proteins and other biomolecules. Copper, for example, is involved in the formation of connective tissue and the maintenance of bone health.
Immune function: Several trace metals, including zinc, copper, and selenium, are important for proper immune function. These metals are involved in the production and function of immune cells and the regulation of inflammation.
Neurological function: Trace metals such as iron, zinc, and copper play critical roles in the development and function of the nervous system. These metals are involved in the production of neurotransmitters, the regulation of neuronal activity, and the maintenance of brain health.
Hormone regulation: Trace metals are also important for the regulation of hormone function. For example, iodine is required for the production of thyroid hormones, which regulate metabolism, growth, and development.

Overall, trace metals play critical roles in various physiological functions and are essential for optimal health. Imbalances or deficiencies in trace metals can lead to a range of health problems, including anemia, immune dysfunction, neurological disorders, and hormonal imbalances.

Studies

Trace metals or trace elements have been extensively studied due to their essential roles in various physiological functions in the body. Here are some examples of studies on trace metals:

Iron: Iron deficiency is a common problem worldwide, particularly in developing countries. Studies have shown that iron supplementation can improve cognitive function and immune function in iron-deficient individuals. On the other hand, excess iron can lead to oxidative stress and damage to various tissues.
Zinc: Zinc deficiency has been associated with impaired growth and development, immune dysfunction, and impaired wound healing. Studies have shown that zinc supplementation can improve immune function and wound healing in zinc-deficient individuals.
Copper: Copper deficiency can lead to anemia and impaired immune function. Excess copper, on the other hand, can lead to oxidative stress and damage to various tissues. Studies have shown that copper supplementation can improve immune function and wound healing in copper-deficient individuals.
Selenium: Selenium deficiency has been associated with increased risk of certain cancers and immune dysfunction. Studies have shown that selenium supplementation can improve immune function and reduce the risk of certain cancers in selenium-deficient individuals.
Manganese: Manganese deficiency has been associated with impaired bone health and impaired glucose metabolism. Studies have shown that manganese supplementation can improve bone health and glucose metabolism in manganese-deficient individuals.
Chromium: Chromium deficiency has been associated with impaired glucose metabolism and increased risk of type 2 diabetes. Studies have shown that chromium supplementation can improve glucose metabolism and reduce the risk of type 2 diabetes in chromium-deficient individuals.
Iodine: Iodine deficiency can lead to goiter, hypothyroidism, and impaired cognitive function. Studies have shown that iodine supplementation can improve thyroid function and cognitive function in iodine-deficient individuals.

Overall, studies on trace metals have highlighted their essential roles in various physiological functions in the body and the importance of adequate intake for optimal health.

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