About Tetrathiomolybdate

Definition

Molybdenum is a trace element considered a micronutrient, meaning a nutrient needed in very small amounts. It is required by almost all living organisms and works as a cofactor for enzymes that carry out important chemical transformations in the global carbon, nitrogen, and sulfur cycles. Thus, molybdenum-dependent enzymes are not only required for the health of people, but also for the health of ecosystems.

Purpose

Molybdenum is an essential trace mineral considered essential in human nutrition. This is because, as tiny as the required amounts are, the consequences of their absence (deficiency) are severe. The active biological form of molybdenum is known as the molybdenum cofactor. It is found in several tissues of the human body and is required for the activity of enzymes that are involved in eliminating toxic substances, including the catabolism of purines, which produces uric acid, formed primarily in the liver and excreted by the kidney into the urine. In addition to being a cofactor of enzymes involved in purine and pyrimidine detoxification, molybdenum also has therapeutic uses, being used in the treatment of:

  • Molybdenum deficiency
  • Molybdenum cofactor deficiency, a disease in which deficiency of the molybdenum cofactor causes severe neurological abnormalities, and mental retardation.
  • Copper poisoning.
  • Improper carbohydrate metabolism.

Recent research findings suggest that molybdenum may also have a role in stabilizing the unoccupied glucocorticoid receptor.

Molybdenum

Age Recommended Dietary Allowance (mcg)
Children 0–6 mos. 2
Children 7–12 mos. 3
Children 1–3 yrs. 17
Children 4–8 yrs. 22
Children 9–13 yrs. 34
Adolescents 14–18 yrs. 43
Adults 19> yrs. 45
Pregnant women 50
Breastfeeding women 50
Food Molybdenum (mcg)
Beans, navy, 1 cup 196
Black-eye peas, 1 cup 180
Lentils, 1 cup 148
Split peas, 1 cup 148
Beans, lima, 1 cup 142
Beans, kidney, 1 cup 132
Beans, black, 1 cup 130
Almonds, 1 cup 46.4
Chestnuts, 1 cup 42.4
Peanuts, 1 cup 42.4
Cashews, 1 cup 38
Soybeans, green, 1 cup 12.8
Yogurt, 1 cup 11.3
Cottage cheese, 1 cup 10.4
Egg, cooked, 1 cup 9
Tomatoes, fresh, 1 cup 9
Veal liver, 3.5 oz. 8.9
Milk, 1 cup 4.9

Description

The body absorbs molybdenum quickly in the stomach and in the small intestine. The mechanism of absorption is uncertain. Following absorption, molybdenum is transported by the blood to the liver and to other tissues of the body. In the molybdate form, it is carried in the blood bound to alpha–macro-globulin and by adsorption to red blood cells. The liver and kidney store the highest amounts of molybdenum. The molybdenum cofactor is made in cells and consists of a molybdenum atom bound to tricyclic pyranopterin molecules, the simplest of which is known as molybdopterin. The cofactor is a component of four main enzymes:

  • Sulfite oxidase. This enzyme catalyzes the transformation of sulfite to sulfate, a reaction that is necessary for the metabolism of sulfur-containing amino acids, such as cysteine.
  • Xanthine oxidase. This enzyme catalyzes the breakdown of nucleotides (precursors of DNA and RNA) to form uric acid, which contributes to the antioxidant capacity of the blood.
  • Aldehyde oxidase. This enzyme is involved in several reactions, including the catabolism of pyrimidines.
  • Xanthine dehydrogenase. This enzyme catalyzes the conversion of hypoxanthine to xanthine, and xanthine to uric acid.

Aldehyde oxidase and xanthine oxidase catalyze hydroxylation reactions involving a number of different molecules with similar structures. Xanthine oxidase and aldehyde oxidase also play a role in the metabolism of drugs and toxins. However, according to the Micronutrient Information Center of the Linus Pauling Institute of Oregon State University, only sulfite oxidase is known to be crucial for human health.

Sources of dietary molybdenum include milk, dried beans, peas, nuts and seeds, eggs, liver tomatoes, carrots and meats. The molybdenum contents are per cup:
  • Navy beans: 196 μg
  • Black-eye peas: 180 μg
  • Lentils: 148 μg
  • Split peas: 148 μg
  • Lima beans: 142 μg
  • Kidney beans: 132 μg
  • Black beans: 130 μg
  • Almonds: 46.4 μg
  • Peanuts: 42.4 μg
  • Chestnuts: 42.4 μg
  • Cashews: 38 μg
  • Yogurt: 11.3 μg
  • cooked egg: 9 μg
  • Green soybeans: 12.8 μg
  • Cottage cheese: 10.4 μg
  • Milk: 4.9 μg
  • Fresh tomatoes: 9 μg
  • Veal liver: 8.9 μg per 3.5 oz-serving
The recommended dietary allowance (RDA) for molybdenum was most recently revised in January 2001:
  • Infants: (0-6 months): 2 μg
  • Infants: (7-12 months): 3 μg.
  • Children (1-3 y): 17 μg

Molybdenum in nutritional supplements is available in the form of sodium molybdate or ammonium molybdate. Molybdenum in food is principally in the form of the organic molybdenum cofactors. The efficiency of absorption of nutritional molybdenum in supplements ranges from 88-93%, and the efficiency of absorption of molybdenum from foods ranges from 57-88%.

Interactions

Studies have shown that high doses of molybdate inhibit the metabolism of acetaminophen in rats. However, it is not known whether this occurs at clinically relevant doses in humans. High doses of molybdate may also lower the absorption of copper. Likewise, high doses of copper may lower the absorption of molybdenum and decrease overall molybdenum levels.

Aftercare

There is only one report of acute poisoning resulting from intake of a dietary molybdenum supplement. The person consumed a total dose of 13.5 mg of molybdenum over a period of 18 days, at an intake rate of 300–800 μg daily, resulting in visual and auditory hallucinations, several petit mal seizures and one grand mal seizure. The subject was treated with chela-tion therapy to remove the molybdenum from his body and his symptoms disappeared after several hours.

Complications Parental concerns

The RDA for molybdenum (17–22 μg for children) is sufficient to prevent deficiency. Although the precise amount of molybdenum required to most likely promote optimum health is not known, there is presently no evidence that intakes higher than the RDA are beneficial. Most people in the United States consume more than sufficient molybdenum in their diets, making supplementation unnecessary. If required, it should be noted that the amount of molybdenum presently found in most multivitamin/mineral supplements is higher than the RDA. It is however well below the tolerable upper intake level of 2,000 μ/day and is generally considered safe.

Precautions

Pregnant women and nursing mothers should be careful not to use supplemental molybdenum in amounts greater than RDA amounts. Those with excess build–up of uric acid in the blood (hyperuricemia) or gout should also exercise caution in the use of supplements. Overall, it is believed that the toxicity of molybdenum compounds appears to be relatively low in humans. The Food and Nutrition Board (FNB) of the Institute of Medicine found little evidence that molybdenum excess was associated with adverse health effects in healthy people. Hyperuricemia and gout–like symptoms have only been reported in occupationally exposed workers in a copper–molybdenum plant and in an Armenian population consuming 10– 15 mg of molybdenum from food daily. Other studies report that blood and urinary uric acid levels were not elevated by molybdenum intakes of up to 1.5 mg/day.

Ammonium tetrathiomolybdate is the chemical compound with the formula [NH4]2MoS4. This bright red ammonium salt is an important reagent in the chemistry of molybdenum and has been used as a building block in bioinorganic chemistry. The thiometallate anion has the distinctive property of undergoing oxidation at the sulfur centers concomitant with reduction of the metal from Mo(VI) to Mo(IV). The salt contains the tetrahedral [MoS4]2− anion. The compound is prepared by treating solutions of molybdate, [MoO4]2− with hydrogen sulfide in the presence of ammonia:[2] [NH4]2[MoO4] + 4 H2S → [NH4]2[MoS4] + 4 H2O The [MoS4]2− anion.

Reactions

The anion is also an excellent ligand. For example, with Ni(II) sources, it forms [Ni(MoS4)2]2−. Much of the chemistry of the thiomolybdate results from studies on salts of quaternised organic cations, such as [NEt4]2[MoS4] and [PPh4]2[MoS4] (Et = C2H5, Ph = C6H5).[3] These organic salts are soluble in polar organic solvents such as acetonitrile and dmf.

The thermal decomposition of [NH4]2[MoS4] leads to molybdenum trisulfide (MoS3), ammonia (NH3) and hydrogen sulfide (H2S), beginning at 155 °C till 280 °C.[1]

(NH4)2(MoS4) → MoS3 + 2 NH3 + H2S

MoS3 then decomposes again to molybdenum disulfide (MoS2) in a broad temperature range from 300 °C to 820 °C. Perfect decomposition to MoS2 under inert gas requires at least 800 °C according to the following reaction, but it can also be achieved at 450 °C, if there is enough hydrogen.[4]

MoS3 → MoS2 + S

MoS3 + H2 → MoS2 + H2S

Related compounds

Several related thio and seleno anions are known including (A = alkali metal cation, [PPh4]+, [NEt4]+)

More complex tetrahedral anions include A2[MoS4-xOx] and A2[WS4-xOx]

Uses

Ammonium tetrathiomolybdate was first used therapeutically in the treatment of copper toxicosis in animals. It was then introduced as a treatment in Wilson’s disease, a hereditary copper metabolism disorder, in humans; it acts both by competing with copper absorption in the bowel and by increasing excretion. Clinical studies have shown ATTM can effectively lower copper levels faster than currently available treatments, and that fewer patients with an initial neurological presentation of their disease who are treated with ATTM experience neurological deterioration [9][10][11]

ATTM has also been found to have an inhibitory effect on angiogenesis, potentially via the inhibition of Cu ion dependent membrane translocation process involving a non-classical secretion pathway.[12] This makes it an interesting investigatory treatment for cancer, age-related macular degeneration, and other diseases featuring excessive blood vessel deposition.[9]

 WTX101 (Tetrathiomolybdate)

WTX101 is a development stage therapy for Wilson Disease that is advancing towards late-stage clinical trials. WTX101 is the proprietary bis-choline salt of tetrathiomolybdate (TTM). TTM is a novel de-coppering agent with a unique mechanism of action that has demonstrated a more rapid and improved control of copper in Wilson Disease patients.

Unlike other de-coppering agents currently available for the treatment of Wilson Disease that form unstable complexes with copper and other metals (e.g., iron and zinc) and are excreted via urine, TTM selectively forms high stability complexes with copper and proteins. These complexes are then primarily excreted via the bile, restoring the normal excretion route of copper that is impaired in patients with Wilson Disease. By rapidly binding and controlling copper in stable complexes, TTM may reduce the risk of mobilizing and transiently increasing the levels of free copper in patients starting de-coppering therapy. The rapid and improved control of copper is very important as high levels of copper cause tissue damage and transient increases in free copper after initiation of therapy is believed to be involved in causing additional tissue damage, especially in the central nervous system.

As a result of the improved control of copper WTX101 is, expected to improve control of the disease as well as reduce the risk of neurological deterioration after initiation of treatment in Wilson Disease patients with neurological disease.

The improved salt formulation of TTM, WTX101, has also been tested in clinical trials in oncology and was found to be safe and tolerable while efficiently lowering copper levels with once daily dosing. A once daily dosing regimen is expected to translate into improved patient compliance in Wilson Disease patients and therefore fewer treatment failures.

WTX101-201 is a Phase 2 clinical trial evaluating the efficacy and safety of WTX101 using an individualized dosing regimen in up to 30 newly-diagnosed patients with Wilson Disease. The study is being conducted at sites in the U.S. and Europe, and will follow patients on WTX101 for six months.

All ongoing WD clinical trials which are currently recruiting:

Phase 2 Study in Newly Diagnosed Wilson Disease Patients with WTX101 (Tetrathiomolybdate)

Patients are being recruited for a Phase 2, multi-center, open-label, study to evaluate the efficacy and safety of WTX101 administered for 24 weeks in newly diagnosed Wilson Disease patients. This study is being sponsored by Wilson Therapeutics.

The study drug, WTX101 (bis-choline tetrathiomolybdate) is a de-coppering agent that is being investigated for the treatment of Wilson Disease. The aim of this study is to confirm that the dosing regimen planned for use in future studies with WTX101 is safe and effective in de-coppering newly diagnosed Wilson Disease patients. The study will be conducted at 6 Wilson Disease expert centers (University of Michigan Hospital, Ann Arbor, MI; Yale University Medical Center, New Haven, CT; UCLA Ronald Reagan Medical Center, Los Angeles, CA; Medical University of Vienna, Vienna, Austria; University Hospital, Heidelberg, Germany; Institute of Psychiatry and Neurology, Warsaw, Poland).

If you are a newly diagnosed Wilson Disease patient you may be eligible to join the trial that is currently underway, if you meet the following criteria:

  • Male or female, aged 18 years or older
  • Have elevated blood free copper levels
  • Treated with chelation or zinc therapy for 28 days or less
  • Have hepatic or neurological symptoms or both
  • In otherwise general good health

The study lasts for 7 months. There are 8 study visits to the study site during this 7 month period and 5 additional study visits with a potential for a nurse to visit you at home to reduce the amount of travel for you. Wilson Therapeutics will pay for your travel expenses.

For further information about this study, please go to https://clinicaltrials.gov/ct2/show/NCT02273596?term=WTx101&rank=1

or https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001703-41/DE#G. To discuss possible participation at any of the United States study centers please contact the University of Michigan Hospital Wilson Disease Clinic by calling 1-800-333-9013. Contact details for all the individual sites are listed in the clinical trials links above.

Key Terms & References

Acetaminophen—An aspirin substitute that works as a pain killer and fever reducer, but does not have anti–inflammatory properties and does not produce the side effects associated with aspirin, such as stomach irritation.

Amino acid—Organic (carbon–containing) molecules that serve as the building blocks of proteins.

Antioxidant—Any substance that prevents or reduces damage caused by reactive oxygen species (ROS) or reactive nitrogen species (RNS).

Antioxidant enzyme—An enzyme that can counteract the damaging effects of oxygen in tissues.

Catabolism—The metabolic breakdown of large molecules in living organism, with accompanying release of energy.

Chelation therapy—The use of a ring–shaped compound called a chelating agent, that can form complexes with a circulating metal and assisting in its removal from the body.

Cofactor—A compound that is essential for the activity of an enzyme.

Blood brain barrier—A physiological mechanism that alters the permeability of brain capillaries, so that some substances, such as certain drugs, are prevented from entering brain tissue, while other substances are allowed to enter freely.

Detoxification—The process of detoxifying, meaning the removal of toxic substances.

Enzyme—A biological catalyst, meaning a substance that increases the speed of a chemical reaction without being changed in the overall process. Enzymes are proteins and vitally important to the regulation of the chemistry of cells and organisms.

Gout—Painful inflammation of the big toe and foot caused by an abnormal uric acid catabolism resulting in deposits of the acid and its salts in the blood and joints.

Hyperuricemia—Abnormally elevated blood level of uric acid, the breakdown product of purines that are part of many foods we eat.

Inflammation—A response of body tissues to injury or irritation characterized by pain and swelling and redness and heat.

Macro minerals—Minerals that are needed by the body in relatively large amounts. They include sodium, potassium, chlorine, calcium, phosphorus, magnesium.

Macronutrients—Nutrients needed by the body in large amounts. They include proteins, carbohydrates and fats.

Metabolism—The sum of the processes (reactions) by which a substance is assimilated and incorporated

  • Children (4-8 y): 22 μg
  • Children (9-13 y): 34 μg
  • Adolescents (14-18): 43 μg
  • Adults: 45 μg
  • Pregnancy: 50 μg
  • Lactation: 50 μg

Micronutrients—Nutrients needed by the body in small amounts. They include vitamins and miberals.

Molybdenum cofactor deficiency—An inherited disorder in which deficiency of the molybdenum cofactor causes deficiency of a variety of enzymes, resulting in severe neurological abnormalities, dislocated ocular lenses, mental retardation, xanthinu-ria, and early death.

Molybdopterin—The chemical group associated with the molybdenum atom of the molybdenum cofactor found in molybdenum–containing enzymes.

Nucleotide—A subunit of DNA or RNA consisting of a nitrogenous base (adenine, guanine, thymine, or cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA), a phosphate molecule, and a sugar molecule (deoxyribose in DNA and ribose in RNA).

Plasma—The liquid part of the blood and lymphatic fluid, which makes up about half of its volume. It is 92% water, 7% protein and 1% minerals.

Protein—Biological molecules that consist of strings of smaller units called amino acids, the “building blocks” of proteins. In proteins, amino acids are linked together in sequence as polypeptide chains that fold into compact shapes of various sizes. Proteins are required for the structure, function, and regulation of the body’s cells, tissues, and organs, and each protein has unique functions.

Purines—Components of certain foods that are transformed into uric acid in the body.

Pyrimidine—A nitrogen–containing, double–ring, basic compound that occurs in nucleic acids.

Recommended dietary allowance (RDA—The levels of intake of essential nutrients judged on the basis of scientific knowledge to be adequate to meet the nutrient needs of healthy persons by the Food and Nutrition Board of the National Research Council/National Academy of Sciences. The RDA is updated periodically to reflect new knowledge. It is popularly called the Recommended Daily Allowance.

Toxic—Harmful or poisonous substance.

Toxin—A poisonous substance, especially a protein, that is produced by living cells or organisms and is capable of causing disease.

Trace minerals—Minerals needed by the body in small amounts. They include: selenium, iron, zinc, copper, manganese, molybdenum, chromium, arsenic, germanium, lithium, rubidium, tin.

Vitamin E—A fat–soluble vitamin essential for good health found chiefly in plant leaves, and wheat.

element— Molybdenum cofactor deficiency disorder is severe and usually results in premature death in early childhood since all of the molybdenum cofactor– dependent enzymes are affected. Isolated sulfite oxidase deficiency only affcets sulfite oxidase activity. Together, molybdenum cofactor deficiency and isolated sulfite oxidase deficiency have been diagnosed in more than 100 individuals worldwide. They are, however, both inherited disorders and there are no documented cases of their ever occurring as a result of dietary molybdenum deficiency.

Resources

BOOKS

Bogden, J., ed. Clinical Nutrition of the Essential Trace Elements and Minerals (Nutrition and Health). Totowa, NJ: Humana Press, 2000.

Challem, J., Brown, L. User’s Guide to Vitamins & Minerals. Laguna Beach, CA: Basic Health Publications, 2002.

Garrison, R., Somer, E. The Nutrition Desk Reference. New York, NY: McGraw–Hill, 1998.

Griffith, H. W. Minerals, Supplements & Vitamins: The Essential Guide. New York, NY: Perseus Books Group, 2000.

Larson Duyff, R. ADA Complete Food and Nutrition Guide, 3rd ed.Chicago, IL: American Dietetic Association, 2006.

Newstrom, H. Nutrients Catalog: Vitamins, Minerals, Amino Acids, Macronutrients—Beneficials Use, Helpers, Inhibitors, Food Sources, Intake Recommendations. Jefferson, NC: McFarland & Company, 1993.

Quesnell, W. R. Minerals : The Essential Link to Health. Long Island, NY: Skills Unlimited Press, 2000.

Wapnir, R. A. Protein Nutrition and Mineral Absorption. Boca Raton, FL: CRC Press, 1990.

ORGANIZATIONS

American Dietetic Association (ADA). 120 South Riverside Plaza, Suite 2000, Chicago, IL 60606-6995. 1-800/877-1600. <www.eatright.org>.

American Society for Nutrition (ASN). 9650 Rockville Pike, Bethesda, MD 20814. (301) 634-7050. <www.nutrition.org>.

Office of Dietary Supplements, National Institutes of Health. National Institutes of Health, Bethesda, Maryland 20892 USA. <ods.od.nih.gov>.

U.S. Department of Agriculture, Food and Nutrition Information Center. National Agricultural Library,10301 Baltimore Avenue, Room 105, Belts-ville, MD 20705. (301) 504-5414. <www.nal.usda.gov>.

Monique Laberge, Ph.D.
Wilson Disease Organization www.wilsondisease.org

 

Reference

Contact

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