Copper and Zinc Metallothioneins for Detoxing & Longevity

Metallothioneins (MTs) detox heavy metals. Metallothioneins are a family of copper/zinc proteins that bind heavy metals. (Superoxide dismutase, a master antioxidant and detoxer of hundreds of chemical toxins and plastics, is also a metallothionein.)

MTs also increase longevity, fight diabetes, prevent neurodegeneration such as in Parkinson’s and Alzheimer’s,

MTs are very low in cancer patients, Alzheimer’s patients, other disease conditions, and the elderly.

Things that increase Metallothioneins: Primarily zinc! But also: copper, sulfur, Cysteine (in beef), exercise, stress, cold exposure, infections, food restriction, gold, blueberries, and bismuth.

Even cadmium and mercury increase MTs (IE, the body makes MTs to detox toxic cadmium and mercury, they are not essential ingredients needed to make MTs, there is a difference. I believe this property also has applicability to Vitamin A increasing ceruloplasmin. This does not mean the body requires the toxin (Vitamin A) to make the detoxer, ceruloplasmin.)

My perception seems to be that the researchers below fall short of any advocacy. They rarely conclude we should be taking copper and zinc. They seem to have an eye for making a drug out of metallothioneins.

Enjoy the excerpts from the 27 studies below.

[Structure and function of metallothionein] 1996

Metallothionein is defined as a low molecular weight protein of high cysteine and heavy metal contents. Although metallothionein does not show any enzymic activities, multifunctional roles in the body have been proposed such as a chelator to harmful heavy metals and excessive essential metals, a scavenger to various radicals and active oxygen species, and a regulator in the cell proliferation process. These biological roles are manifested through the mercaptide bond (metal-sulfurbond) that characterize metallothionein. All metals bound to metallothionein are coordinated tetrahedrally by cysteinyl sulfurs and this coordination structure forms two clusters consisting of 11 cysteinyl residues and 4 cadmium and/or zinc (cluster alpha), and 9 cysteinyl residues and 3 metals (cluster beta). Metallothionein can be induced by metals, organic chemicals and various kinds of stress and non-chemical stimulation. The gene structure and the regulation mechanisms for its expression are well understood and the regulator region is widely used to control fused structure genes. The biological roles of metallothionein are now studied using transgenic and MT-gene knock out mice.”

“a chelator to harmful heavy metals and excessive essential metals”

Needed to make MT’s: Sulfur.
Cysteine (in beef)

Regulation of metallothionein gene expression 1990

The metallothioneins are small, cysteine-rich proteins that have the capacity for high affinity binding of heavy metal ions, and whose synthesis is regulated by metal ion concentrations. These properties suggest that they play pivotal roles in the metabolism of the relatively nontoxic essential metals (zinc and copper), as well as toxic heavy metals (cadmium), a concept supported by a variety of studies of cells in culture, as well as in intact animals. Expression of the metallothionein genes may have important implications in the nutritional status of the animal, in its response to stresses (inflammation, heavy metal toxicity), and in embryonic, fetal and neonatal development. The complementary DNAs and genes that encode the metallothioneins have been cloned and analyzed from a wide variety of eukaryotes. Striking features of the metallothioneins include: their high degree of amino acid sequence similarity (including conservation in the placement of cysteine residues in the molecule reflecting their function in metal binding); a conserved tripartite gene structure; and their transcriptional induction by metal ions, as well as other hormonal and environmental stimuli. The precise mechanisms and biochemical pathways by which cells transduce environmental signals into transcriptional induction of the metallothionein genes are beginning to be defined. Recent studies indicate that metal effects are exerted via positive trans-acting factors induced to interact with cis-acting DNA sequences in the promoter, in turn leading to transcriptional induction. However, the metallothionein gene promoter is structurally complex, and contains binding sites for a variety of nuclear proteins that likely regulate basal as well as induced levels of expression of these genes. Recent studies also suggest the possible involvement of post-transcriptional processes in the regulation of metallothionein levels in the cell. Furthermore, evidence of striking differences in the levels of metallothionein gene expression among various cell types in vivo have recently been documented. Although several detailed reviews of the metallothioneins have been published recently, this review will focus, in large part, on the molecular biology of the metallothioneins, with particular emphasis on recent advances in our understanding of the mechanisms regulating expression of these interesting and important genes. Given the large volume of literature on the metallothioneins and the space limitations of this review, it is impossible to comprehensively cite the studies of each of my colleagues who have contributed so much to this field. Instead the reader is often directed to reviews of this subject for much of the earlier literature, and emphasis is placed on more current publications in this field.”

Metallothionein-protein interactions 2013

“The intercourse of MTs with zinc-dependent enzymes and transcription factors is capable to activate/deactivate them, thus conferring MTs the role of metabolic and gene expression regulators.”

In other words, zinc is a gene regulator.

Significance of metallothioneins in aging brain 2014

“Metallothioneins (MTs) are low molecular weight, zinc-binding, anti-inflammatory, and antioxidant proteins that provide neuroprotection in the aging brain through zinc-mediated transcriptional regulation of genes involved in cell growth, proliferation, and differentiation.”

“In general, MT-1 and MT-2 induce cell growth and differentiation, whereas MT-3 is a growth inhibitory factor, which is reduced in Alzheimer’s disease. MTs are down-regulated in homozygous weaver (wv/wv) mice exhibiting progressive neurodegeneration, early aging, morbidity, and mortality. “

“This report provides recent knowledge regarding the therapeutic potential of MTs in neurodegenerative disorders of aging such as Parkinson’s disease and Alzheimer’s disease.”

Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson’s disease 2005

“Parkinson’s disease is characterized by a progressive loss of dopaminergic neurons [from low copper] in the substantia nigra zona compacta, and in other sub-cortical nuclei associated with a widespread occurrence of Lewy bodies. The cause of cell death in Parkinson’s disease is still poorly understood, but a defect in mitochondrial oxidative [from low copper] phosphorylation and enhanced oxidative [from low copper] and nitrative stresses have been proposed.”

Diabetes and metallothionein 2007

Diabetes is a widespread disease, and its development and toxic effects on various organs have been attributed to increased oxidative stress. Metallothionein (MT) is a group of intracellular metal-binding and cysteine-rich proteins, being highly inducible in many tissues. Although it mainly acts as a regulator of metal homeostasis such as zinc and copper in tissues, MT was found to be a potent antioxidant and adaptive (or stress) protein to protect cells and tissues from oxidative stress. Studies showed that zinc-induced or genetically enhanced MT synthesis in the pancreas prevented the development of spontaneous or chemically-induced diabetes. Genetically or pharmacologically enhanced MT expression in various organs including heart and kidney provided significant protection from diabetes-induced organ dysfunction such as cardiomyopathy and nephropathy. These studies suggest that MT as an adaptive protein can prevent both diabetes development and diabetic complications. This mini-review will thus briefly describe MT’s biochemical features and then summarize the data on the protective effect of MT against diabetes and diabetic complications. In addition, the coordinative role of MT with zinc in the prevention of diabetes and its complications will also be discussed.

Zinc/Copper MT’s, prevents diabetes, helps protect the heart and kidney from diabetic damage.

Metallothionein and the biology of aging 2011

“MT is one of just a handful of proteins that, when overexpressed, has been demonstrated to increase mouse lifespan.” –longevity

“MT also protects against development of obesity in mice provided a high fat diet…”

Elevated metallothionein expression in long-lived species 2022

“Metallothioneins (MTs) are a family of small (6-7 kDa)
cysteine-rich metal-binding proteins that have been
extensively studied for their function in homeostatic
regulation of zinc (Zn) and copper (Cu) as well as for
their role in heavy metal detoxification.”

[Metallothionein] 1997

“Metallothionein is a low-molecular weight protein involved in resistance to toxicity of heavy metals.”

Nutritional and environmental factors affecting metallothionein levels 1979

A number of elements including zinc, cadmium, mercury and copper will enhance the synthesis of MT, but only zinc and cadmium are deposited with this protein at higher levels than with other proteins in the liver when these are given orally. However, mercury and copper are deposited with MT in the kidney regardless of whether given orally or by injection. As the level of zinc is increased in the diet a corresponding increase of zinc concentration occurs only in the MT fraction of tissue cytosols. Zinc disappears from the MT fraction to the supplementation levels within 3 to 4 days when rats which have been fed a high zinc diet are changed to a zinc deficient diet. The evidence indicates that MT is involved with zinc metabolism. The half-life of MT is longer when cadmium is used to induce its synthesis than when zinc is used. Dietary sulfur deficiency limits the synthesis of MT. Various stresses, in which strenuous exercise, cold environment, and CC14 injection were most effective, and infections were found to enhance MT synthesis, suggesting a role for it in the defense mechanism.

IE, take zinc and copper. And sulfur. And exercise, and get cold exposure.

The binding of Gold(I) to metallothionein 1980

Interactions between metallothionein and trace elements

Metallothionein is an important metal-binding protein which occurs in varying amounts in a wide range of tissues but particularly in liver, kidneys, intestine and pancreas. Synthesis of the protein is induced by zinc and copper and also by cadmium and many other non-essential elements. The concentration of the protein in tissues depend on zinc and copper status and on patho-physiological state. A variety of stress factors stimulate metallothionein synthesis, particularly in liver. The turnover rate of metallothionein in tissues is relatively high but depends to a large extent on its metal content. There has been much speculation as to the function of the protein and one important role appears to lie in the cellular detoxification of copper, zinc and other metals. Metallothionein also appears to participate in metabolic interactions between zinc and copper. The protein occurs in small amounts in blood and urine and assay of these concentrations may be used in the assessment of trace element status.

” Synthesis of the protein is induced by zinc and copper…”

IE, take zinc and copper for increased MT and detox.

The protective role of metallothionein in copper overload: I. Differential distribution of immunoreactive metallothionein in copper-loaded rat liver and kidney

The protective role of metallothionein in copper-overload: II. Transport and excretion of immunoreactive MT-1 in blood, bile and urine of copper-loaded rats

“The regulation of copper homeostasis in copper overloaded animals occurs by excretion of excess of the metal in bile and urine, which may be facilitated by metallothionein (MT) a copper binding protein.”

Influences of gold on zinc, copper and metallothionein kinetics in liver and kidney of the rat 1996

“4. The results suggest that gold by itself induces an increase of MT-like peptides in the kidney cytosol, which was accompanied by an increase in the concentration of Cu mainly bound to these MT-like peptides.”

Gold increases MT.

The status of zinc, copper, and metallothionein in cancer patients

“the levels of metallothionein in normal and in malignant human livers are 471 and 75 micrograms/g, respectively.”

“Moreover, the activity of superoxide dismutase [a MT] to remove free oxygen radicals is lower in malignant tissues.”

Metallothionein–aspects related to copper and zinc metabolism

“Metallothionein is a cysteine-rich, low molecular weight protein that binds zinc, copper and cadmium. It is inducible in liver, kidney and intestine by glucocorticoids, changes in the dietary zinc supply, acute administration of various metals, food restriction, infection, stress and endotoxin treatment. Regulation of synthesis involves altered gene expression.”

Food restriction, stress, and infections increase MT.

Biological and health implications of toxic heavy metal and essential trace element interactions 1987

Human civilization and a concomitant increase in industrial activity has gradually redistributed many toxic metals from the earth’s crust to the environment and increased the possibility of human exposure. Among the various toxic elements, heavy metals cadmium, lead, and mercury are specially prevalent in nature due to their high industrial use. These metals serve no biological function and their presence in tissues reflects contact of the organism with its environment. They are cumulative poison, and are toxic even at low dose. Studies of metabolism and toxicity of these elements have revealed important interactions between them and some essential dietary elements like calcium, zinc, iron, selenium, copper, chromium, and manganese. In general, a deficiency of these essential elements increases toxicity of heavy metals, whereas an excess appears to be protective. While most of the observations are on laboratory animals, limited human data are in agreement with the results of animal experiments. These suggest that the dietary presence of the essential elements may contribute to the protection of man and animal from the effects of heavy metal exposure, while their deficiency may increase toxicity. Appropriate dietary manipulation thus may be valuable in the prevention and treatment of heavy metal toxicity.”

Conclusion: Good metals detox bad metals.
Good: “calcium, zinc, iron, selenium, copper, chromium, and manganese”
Bad: “cadmium, lead, and mercury”

Evidence for a Potential Role of Metallothioneins in Inflammatory Bowel Diseases

Increase in metallothionein produced by chemicals that induce oxidative stress

Dietary Supplementation of Blueberry Juice Enhances Hepatic Expression of Metallothionein and Attenuates Liver Fibrosis in Rats 2013

Blueberry juice consumption significantly attenuates CCl4-induced rat hepatic fibrosis, which was associated with elevated expression of metallothionein (MT), increased SOD activity, reduced oxidative stress, and decreased levels of α-SMA and Col III in the liver.”

[Role of metallothionein in cancer chemotherapy] 1994

“Preadministration of bismuth subnitrate, an MT inducing drug, significantly reduced side effects of antitumor drugs without affecting antitumor activity of the drugs.”

Bismuth, or Pepto Bismol, may increase MT.

The ATP-metallothionein complex

“The interaction of MT with two critical cellular ligands, i.e., GSH and ATP, and ensuing effects on zinc transfer and reactivity suggest that MT is not merely a cellular zinc buffer but, rather, actively participates in zinc distribution.”

Or, copper, needed for ATP, helps distribute zinc.

The role of metallothionein interactions with other proteins

“Metallothionein (MT) is a protein involved in numerous key processes, and the most important include zinc ion homeostasis, detoxification of heavy metals, and protection against oxidative stress. … Possibly in the future MT will become a therapeutic agent, which will result in a breakthrough in the field of pharmacy and medicine.”

Challenging conventional wisdom: single domain metallothioneins

“Metallothioneins (MT) are a family of small cysteine rich proteins that have been implicated in a range of roles including toxic metal detoxification, protection against oxidative stress, and as metallochaperones are undoubtedly involved in the homeostasis of both essential zinc and copper. While complete details of all possible cellular functions are still unknown…”

Metallothioneins (MTs) in the human eye: a perspective article on the zinc-MT redox cycle

“Metallothioneins (MTs) are zinc-ion-binding proteins with a wide range of functions, among which are neuroprotection, maintenance of cellular zinc homeostasis, and defense against oxidative damage and inflammation. The human eye is enriched in MTs, and multiple isoforms may contribute to distinct antioxidant defense mechanisms in various ocular tissues.”

“Levels of MTs decrease with aging and disease…”

“This state is also observed with increased oxidative stress and inflammation, suggesting that the antioxidant function of MTs has been impaired.”

The Functions of Metamorphic Metallothioneins in Zinc and Copper Metabolism 2017

“The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn2+ and Cu⁺ match the biological requirements for controlling-binding and delivering-these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn2+ and Cu⁺. How this knowledge translates to the function of other families of MTs awaits further insights…”