Another piece to the puzzle?? Metallothionein

[Gabes-Apg]

Another possible piece to the puzzle to those with multiple issues.
The following is from the book: Nutrient Power, Heal your biochemistry and heal your brain
Wiliam J Walsh, PHd (published 2012)

this topic might be worthy of further research for those that are struggling to attain wellness. I decided to type out and share this section, as when I read the list of processes that Metallthionein is involved in, so many of these issues are very common to this group and are issues that many have trouble resolving.
it is a little bit scientific, albeit worth the read due to the links to inflammation, leaky gut, and digestion, Candida etc!

(IMO this is one of a possible 30-40 elements that wakes the angry MC bear in us. And is also one of the elements that hinders remission for many)
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Metallothionein

Metallothionein, (MT) proteins play an important role in mental health. Poor MT function has been associated with ADHD, autism, schizophrenia, Alzheimers disease, and Parkinson’s disease. MT proteins perform a myriad of vital functions including the following processes;
- Early brain cell development
- Powerful antioxidant capability
- Detoxification of mercury and other toxic metals
- Reduction of inflammation after injury or illness
- Enhanced efficiency of the intestinal and blood brain barriers
- Development and functioning of the immune system
- Delivery of Zinc to cells throughout the body
- Homeostatic control of zinc and copper levels in blood
- Prevention of yeast overgrowth in the intestines
- Regulation of stomach acid pH
- Taste discrimination by the tongue
- Protection of enzymes that break down casein and gluten
- Zinc signalling in brain cells
- Regulation of tumor suppression genees
- Transcription factor regulation

The Metallothionein Family of Proteins
Metallothioneins are short, linear, cystein-rich proteins composed of between 61-68 amino acids. All human MTs contain 20 cysteines and have an ‘S’ configuration with extraordinary metal binding capability. There are four varieties of metallothionein proteins. MT-I and MTII are found throughout the body, and their functions include regulation of zinc and copper levels, development of neurons and synaptic connections, enhancement of immune function, and protection against toxic metals.
MTIII is a necessary factor in the pruning and growth inhibitory phases of brain cells development.
MTIV regulates stomach acid pH and enables taste discrimination by the tongue.
Synthesis of MT proteins involves genetic expression of thionein (induction) followed by loading of thionein with metal atoms. MT-I and MT-II take on seven zinc atoms, while MT-III typically contains four copper atoms and 2 zinc atoms. MT proteins are generated in response to injury, illness, emotional stress or exposure to toxic metals. They represent a major antioxidant system in the body.
MT proteins are found at high levels in four brain areas: hippocampus, amygdale, pineal gland and cerebellum. The hippocampus is essential to cognition, speech, learning, memory and behavioural control. The pineal gland produces melatonin that assists sleep. The cerebellum enables smooth physical movements. Weakened MT function could result in problems in any of these areas.

Brain Development
In infancy the brain has a high population of small, densely packed neurons. MT-III plays an important role in pruning of brain neurons during early development, which enables the remaining brain cells to grow and develop synaptic connections. In addition, MT-III is the primary inhibitory factor that stops the growth process when brain cells reach optimal size. An early MT-III dysfunction would be expected to result in the following:
- Incomplete pruning
- Areas of densely packed underdeveloped neurons
- Increased brain volume and head diameter
All of these phenomena have been reported in autism spectrum disorders. This understanding has led to MT-Promotion therapies aimed at completion of brain development in children. These therapies are also under development for Alzheimer’s disease since extremely low MT levels have been observed in this disorder.

Detoxification of Heavy Metals
Metallothioeins are heavy metal magnets. They bind mercury, lead, cadmium, and other toxic metals tightly and render them relatively harmless. Deficiencies in metallothionein functioning would, therefore, be expected lead to an increased burden of these dangerous substances. MT proteins work in tandem with GSH and selenium. Metal atoms are transferred into thionein by reduced GSH to form Zn7MT. However, glutathione disulfide (GSSG) enables the release of zinc in exchange for another atom, for example, mercury, cadmium, lead or copper. The cellular redox state of GSH determines the direction of the zinc transfer. For example, GSH efficiently binds to toxic mercury but has a limited capacity. When more than 10% of reduced GSH has been converted to GSSG (oxidized GSH) the GSSG activates MT to enable its participation in the sequestering toxic metals. In essence, GSH levels have been significantly depleted. Selenium increases the kinetics of mercury transfer into MT by about 50%. Optimal protection against toxic metals requires proper amounts of GSH, MT, and selenium, and I refer to them as The Three Musketeers.

Intestinal and Blood-Brain Barriers
MT-I and MT-II are present in very high concentrations in intestional mucosa, forming a barrier to penetration of mercury, lead, and other toxins in the portal blood stream. With respect to toxic metals, the expression leaky gut often means a failure of MT to function normally. In healthy persons, toxic metals in the diet are sequestered in mucosal MT, which is sloughed off every 5 to 10 days to be left harmlessly in the stool. It is impossible to avoid significant exposures to toxic metals in normal living, and the MT system is needed every day. For example, the average amount of mercury in a typical adult diet is about 20 micrograms/day, with higher amounts for high seafood diets. The average amount of mercury entering the body from breathing (in the USA) is one microgram/day.
MT proteins are in high concentration at the blood brain barrier (BBB) and represent the primary protection against toxic metals from entering the brain. In addition, MT proteins within the brain assist in sequestering any toxins that penetrate the BBB. It has been estimated that in healthy adults 90% of the mercury in the diet is prevented from entering the portal blood stream that flows to the liver. In the liver, MT, GSH and other antioxidants bind to about 90% of the mercury that has penetrated the intestinal barrier. The MT in BB is believed to be about 90% efficient in stopping mercury’s access to the brain. IN summary, less than one ingested mercury atom (or compound) in 1,000 is able to enter the brain of healthy persons. However if MT function is weak or disabled, toxic metals can wreak havoc in the brain by altering neurotransmitter synthesis, destroying myelin, producing inflammation, increasing oxidative stress, and, in some cases, killing brain cells. Two studies have indicated MT levels are less than one third of the normal concentration in Alzheimers patients and this may be a factor to the relentless death of brain cells in this disease.

Metallothionein and the GI Tract
The highest concentrations of MT proteins in the body are in the GI tract. An important role of MT in the intestines is the donation of zinc for synthesis of enzymes carboxypepidase A and aminopedidase, which are needed to break down casein, gluten and other proteins from food. Zinc is also required for proper functioning of dipeptidyl peptidaseIV, which breaks down gliadin, casomorphines and other proline containing proteins. A significant impairment in MT function could cause incomplete breakdown of casein, gluten, casomorphins, etc which would result in severe food allergies. In my experience, about 85% of the autism population reports major lessening of symptoms after a gluten-free/casein free diet.
MT has other important roles in the GI tract. For example MT is an important defence mechanism against intestinal inflammation and diarrhea. In addition, MT proteins kill Candida and tend to prevent yeast overgrowth. Stomach parietal cells are rich in MT-IV proteins that promote formation of hydrochloric acid (HCl). MT-IV on the surface of the tongue enables taste discrimination.

Metalliothionein and Immune Function
The importance of metallothionein in immune function has been known for more than 20 years. MT proteins are the primary vehicle for delivery of zinc to cells, and zinc deficiency can severely impair the immune system. In animal studies, reduced levels of MT and zinc during gestation resulted in atrophy of thymic and lymphoid tissues and greatly weakened immune response to infections. Experiments involving knockout mice (a strain of rodent with one or more genes removed – in this case an MT gene) show severely impaired immunity
Weak MT activity can result in a premature transition from cell-mediated immunity to humoral response and can result in a decreased amount of circulating T cells. MT also enhances immune function through its role as an efficient scavenger of free radicals. When the body is under attack by bacteria or viruses, macrophages and neutrophils work overtime to destroy the invaders. Once they have engulfed and killed an intruder, excess hydrogen peroxide is left behind, and MT is effective in mopping up this toxic oxidizing chemical.

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some initial reading thus far, there are quite a few published studies about this and inflammation (mostly in animals)
because it is nutrient/mineral deficiency linked, it is not getting the research dollars to create a med to fix it.

The studies follow the storyline that Metallothionein deficiency = increased inflammation and this is linked to things like depression, diabetes, Alzheimer etc.

http://connection.ebscohost.com/c/artic ... betic-mice
The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

[tex]

Hi Gabes,

I know nothing about metallothionein, so for all I know, most of what that author has written may be useful, but in view of some of what he has written, I'm not sure that he's a straight shooter. Consider this text from the info that you posted, for example:

Metallothionein and the GI Tract
The highest concentrations of MT proteins in the body are in the GI tract. An important role of MT in the intestines is the donation of zinc for synthesis of enzymes carboxypepidase A and aminopedidase, which are needed to break down casein, gluten and other proteins from food. Zinc is also required for proper functioning of dipeptidyl peptidaseIV, which breaks down gliadin, casomorphines and other proline containing proteins.

None of the 3 enzymes that he lists are actually produced by the human body, though he seems to imply as much in his text. Those enzymes can be found in OTC enzyme concoctions sold to minimize the reactions of celiacs who accidentally ingest small amounts of gluten, for example, but they are not endogenous to Homo sapiens' digestive systems. Therefore, the sentence:

A significant impairment in MT function could cause incomplete breakdown of casein, gluten, casomorphins, etc which would result in severe food allergies.

is bogus. No human can digest the gliadins nor the glutenins in wheat gluten, because our species is incapable of producing the enzymes needed to break down those peptides.

Tex

[Gabes-Apg]

No human can digest the gliadins nor the glutenins in wheat gluten, because our species is incapable of producing the enzymes needed to break down those peptides.

thats why i thought the Metallothionein theory presented had creditibility... the inability to breakdown those peptides is getting worse? or is having a greater effect on the body. (ie causing more inflammation compared to 30 years ago)

also that the body is not clearing other toxins properly, like mercury, the inflammation, the leaky gut and the increased level of toxins is having greater detrimental impact on the immune system, adrenals, cell health, the brain etc etc. and ingredients like gluten and casein are having more of an damaging impact

[tex]

the inability to breakdown those peptides is getting worse? or is having a greater effect on the body. (ie causing more inflammation compared to 30 years ago)

No human who ever lived could digest gluten. We didn't evolve to digest it. For many people, it just passes through their gut and their immune system doesn't notice it (their immune system is asleep at the wheel). But our immune system properly recognizes it as a foreign element, and reacts against it.

Everyone experiences increased intestinal permeability after ingesting gluten. Everyone. But only those who develop a sensitivity to it progress to the stage where the tight junctions open wide enough to cause the problems associated with leaky gut.

The reason why gluten sensitivity is a steadily-increasing problem is simply because gluten concentrations in food (primarily in flour), and the total amount of gluten in the diet (more gluten-containing carbs in the diet), continues to increase. People love to eat gluten, so they eat more and more of it with each passing year. It's that simple. It's a problem of gluten-gluttony. When I was a kid, pizza (for example) did not exist in many parts of this country — at least we had certainly never heard of it in my neck of the woods. You would have had to go to the big cities to find it, and only people of Italian origin were familiar with it. How many pounds/tons of the stuff do most people eat annually these days?

Tex

[Gabes-Apg]

He might be wrong about the gluten and casein, albeit the other issues mentioned have creditibility.
More so for those where there is MTHFR and Pyrrole cell issues.
If people have MT deficiency, Vit D3 supplementation won't be enough to resolve the issues.

[tex]

Gabes,

I certainly wouldn't argue that point. As I said, I know nothing about metallothionein.

Tex

[nerdhume]

Looking up more info:
http://metabolichealing.com/metallothio ... leaky-gut/

One of the primary reasons that taking high doses of zinc stops severe diarrhea is due to the immediate increase in metallothionein from increased zinc status.

Then I wondered how much is a 'high dose of zinc'? Was following up on some research about the relationship of zinc and MT...ran across this:
http://www.mayoclinic.org/drugs-supplem ... b-20060638
Apparently Mayo promotes zinc for many problems.

[Gabes-Apg]

Theresa,
The link of MT to a few deficiencies that are very much linked to MC issues is why I did the post.
The other aspect that many MC'ers have is Candida, maybe the approach should be amino acids, zinc and Vit C.

I have been taking high doses of Vit C, Magnesium and Zinc to balance histamines.
For years I have been using zinc liquid on gums and teeth to reduce bacteria.

I always knew that bone broth was excellent for healing leaky gut and providing essential amino acids. The information above reiterated the importance so far as protecting the brain.

I also hoped it would help people understand why taking the necessary time (ie years) to allow good gut healing to occur. Long term wellness is reliant on it.

[tex]

I also hoped it would help people understand why taking the necessary time (ie years) to allow good gut healing to occur. Long term wellness is reliant on it.

It always bothers me how so many new members will cut their main food sensitivities out of their diet, and as soon as they begin to improve (before any significant healing actually occurs), they want to begin adding all sorts of foods back into their diet, and one of the more popular early selections to add back is often salads, which are loaded with abrasive fiber.

Tex