Metallothionein

Metallothionein (MT) is a small cysteine-rich protein thought to play a critical role in cellular detoxification of inorganic species by sequestering metal ions that are present in elevated concentrations. We demonstrate here that metallothionein can play an important role at the other end of the homeostatic spectrum by scavenging an essential metal in a mouse fibroblast cell line that has been cultured under conditions of extreme zinc deprivation (LZA-LTK⁻). These cells unexpectedly produce constitutively high levels of metallothionein mRNA; however, the MT protein accumulates only when high concentrations of zinc are provided in the media. Until this MT pool is saturated, no measurable zinc remains in the external media. In this case, zinc deprivation leads to amplification of the MT gene locus in the LZA-LTK⁻ cell line. Furthermore, the intracellular zinc levels in the fully adapted cells remain at the normal level of 0.4 fmol zinc/cell, even when extracellular zinc concentration is decreased by 2 orders of magnitude relative to normal media.

Why is Metallothionein Important?

Required for pruning, growth and growth-inhibition of brain cells in early development,
Prevents Hg, and other metal toxics from passing intestinal and blood/brain barriers,
Required for homeostasis of Cu and Zn,
Supports immune function,
Major antioxidant system in body & brain.
MT functioning can be disabled by severe oxidative stres

Metallothionein - MT Promotion Nutrient

The scientific literature clearly indicates that most of the body's MT is induced by zinc, with glutathione (GSH) needed for loading apo-MT with zinc and glutathione disulfide (GSSH) required for redox exchange. Selenium and the GSH/GSSH redox couple enhance

delivery of Zn to cells
sequestering of mercury and other heavy metals

The equilibrium constants for binding of MT to heavy metals are remarkably large; with the net result that Zn-MT is a "magnet" for these toxic metals.

MT proteins are composed of 14 amino acids and zinc. Many autism-spectrum patients are unable to efficiently cleave dietary proteins into the individual amino acids needed for MT synthesis. Our formulation provides all 14 amino acids, in the proportion found in MT. The large amounts of cysteine required for MT synthesis can be supplied in the form of oral GSH which breaks down in the G.I. tract with minimal side effects.

Clinical Testing Procedures

MT-promotion therapy is recommended only for patients with disturbed metal metabolism. Key laboratory tests include serum copper, plasma zinc, and serum ceruloplasmin. In healthy individuals, the Cu/Zn ratio usually ranges between 0.8 and 1, and the amount of free copper (unbound by ceruloplasmin) ranges from 5 to 25 mcg/dL. In addition, the presence or absence of symptoms of copper overload and zinc deficiency can also aid diagnosis. Meaningful assays require acid-etched trace-metal-free sample tubes and avoidance of trace mineral supplements for 24 hours before sampling.

Other essential tests required for full evaluation include blood counts, tests of liver and kidney functions, along with an evaluation of thyroid function. Testing plasma ammonia is highly recommended prior to treatment because of the high prevalence of elevated ammonia levels in patients with autism/PDD and related disorders.

Also, a full evaluation of intestinal microflora, including both stool comprehensive parasitology (aerobic bacteria, yeast, and parasites) and urine organic acid test is recommended prior to the initiation of any therapy.

Other tests that may be useful include plasma sulfate and plasma reduced glutathione levels prior to the initiation of therapy.

Treatment for Patients Found to Have Metallothionein Dysfunction

A good trial of the gluten-free, casein-free diet (at least 6 months) is highly recommended.

Step 1
1. Gut Clean-up - restore good levels of friendly bacteria and reduce overgrowths of unfriendly organisms such as Clostridia and yeast
2. Supporting Nutrients - exact nutrients determined by testing
3. Reduction of elevated plasma ammonia (if necessary)
4. Aggressive zinc pre-loading
5. DMSA alone until very little mercury, lead or tin is excreted in urine (if necessary)
Step 2 - MT Promotion Protocol
1. Phase 1: Zinc Loading: Aggressive supplementation with Zn and augmenting nutrients for 4 to 8 weeks is recommended. Sensitive patients may require gradual build-up of Zn dosage. Plasma zinc levels should be greater than 100 mcg/dL prior to Phase 2 to minimize irritability side effects. Zinc dosages vary with body weight. A helpful rule of thumb for small patients is to provide a daily mg dosage of Zn equal to weight (lbs) plus 15-20 mg. For example, a 40 lb child would receive 55-60 mg/day during Phase 1. In addition, we recommend the following augmenting nutrients be given with the Zn: Pyridoxal-5-Phosphate, Manganese Gluconate, and Vitamins C and E. Also, Taurine may be used for patients with seizure tendencies. We have developed a compounded supplement for Phase 1, which we call the "Metabolic Primer".
2. Phase 2: After Phase 1 is completed, GSH, Se, and the 14 amino-acid constituents of MT are introduced gradually, as tolerated. These nutrients are available in a compounded blend called the MTP supplement. Continuation of casein/gluten-free diets, probiotics, the Metabolic Primer, and other ongoing therapies is recommended.

Objectives of MT-Promotion Therapy

Promotion of the MT protein system is expected to provide many benefits to autism-spectrum patients, including:

elimination of toxic metals
protection against future toxic exposures
normalization of the G.I. tract
improved behavior control
improved immune function
enhanced development of brain neurons and synaptic connections

The first 5 benefits may be attainable in the first year of treatment, regardless of the patient's age. However, the rate of formation of new synaptic connections declines rapidly with age, and early intervention is critically important for development of speech, cognitive advancement, etc. Great patience is needed in treatment of older children who can be expected to progress at a relatively slow rate. For example, it may require years for a 10 year old to achieve the same cognitive progress achieved by a 2 year old in a few weeks. Behavioral therapies, which shower the brain with impulses and promote neuronal development are especially recommended in conjunction with Metallothionein Promotion therapy.

References.

http://www.asianjournalofchemistry.co.in/User/ViewFreeArticle.aspx?ArticleID=23_1_1

https://www.ncbi.nlm.nih.gov/pubmed/12022471

https://www.ncbi.nlm.nih.gov/pubmed/10605938

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634463/

https://www.ncbi.nlm.nih.gov/pubmed/10605938

https://www.ncbi.nlm.nih.gov/pubmed/12498322

https://www.ncbi.nlm.nih.gov/pubmed/28353636

https://www.ncbi.nlm.nih.gov/pubmed/10774929

https://www.ncbi.nlm.nih.gov/pubmed/15892631

https://www.ncbi.nlm.nih.gov/pubmed/11123969

https://www.ncbi.nlm.nih.gov/pubmed/10049512