Molybdenum in Human Health
Therapeutic Uses of Molybdenum
Molybdenum is an essential trace element and is a component of vitamin and mineral supplements. Some therapeutic uses of molybdenum compounds are described in this section.
Treatment of anaemia
Magnesium molybdate in daily doses of 0.06-0.20 g Mo has been used in the treatment of various conditions including anaemia and as a general tonic for restoring appetite after convalescence [Vignoli and Defretin, 1963].
Vignoli L.and Defretin, J. P., Biologie medicale, 1963, 52, 319.
A sustained-release preparation of a molybdenised iron(II) sulfate is capable of promptly correcting iron deficiency anaemia and is prescribed for this purpose [Mouratoff and Batterman, 1961; Stevenson, 1962; Rudolph et al., 1963].
Mouratoff, G. L. and Batterman, R. C., J. New Drugs, 1961,1,157.
Stevenson, T. D., Current Therapeutic Research, 1962, 4, 107.
Rudolph, I., Ongchangco, M. N. and Fink, H., Current Therapeutic Research, 1963, 5, 517.
Prevention of dental caries
It is well known that fluoride is effective against the development of dental caries in experimental animals and in human beings. There is evidence that trace elements, particularly molybdenum, in the water supply and in food, enhance the cariostatic effect of fluoride [Schutte, 1964]. For example, children fed on vegetables from the molybdenum-rich Napier area of New Zealand had fewer caries than children from other areas. Similar epidemiological studies in Europe and the United States have confirmed the cariostatic effect of molybdenum [Lossee and Bibby, 1970; Hadjimarkos, 1966; Anderson, 1969; Jenkins, 1967; Lossee and Adkins, 1971].
Schutte, K. H., The Biology of the Trace Elements, Crosby Lockwood and Son Ltd., London, 1964, 92.
Lossee, F. L. and Bibby, B. G., New York State Dental Journal, 1970, 36, 15.
Hadjimarkos, D. M., Anderson, R. J., Caries Res., 1969, 3, 75.
Arch. Environ. Health, 1966, 13, 102.
Jenkins, G., British Dental Journal, 1967, 435, 500, 545.
Lossee, F. L. and Adkins, B. L., Geol. Soc. Amer., Mem., 1971, 123, 203.
The incidence of dental caries is lower in parts of Hungary than would be expected from the fluoride content of the water supply. On investigation it was found that the molybdenum content of the drinking water was high. Further studies from New Zealand, from the cities of Hastings and Napier, showed that the incidence of caries in Napier was significantly less than in Hastings, although both towns had the same water supply. However, the inhabitants of Napier ate vegetables grown in soil that had been under the sea until raised by an earthquake 30 years ago; the concentration of molybdenum was much higher in this soil than in that around Hastings. The molybdenum content of the teeth of boys living in Napier was higher than that of boys in Hastings, although the hair content of molybdenum in boys from both cities was the same. Another piece of evidence suggesting that deficiency of molybdenum plays a part in dental caries is that in Somerset UK the incidence of caries is high in children from areas where the cattle suffer from molybdenum deficiency.
Many workers have given molybdenum to animals and confirmed its anti-cariogenic properties, although in some cases the dose of molybdenum was high. It is not yet established what is the effective anti-cariogenic dose of molybdenum, at what stage in tooth formation it acts, or whether there is any relation between fluoride and molybdenum. Molybdenum has been shown to reduce the solubility of teeth in acid and also to reduce the acid output by the salivary glands. It is more likely that molybdenum acts by affecting the morphology of teeth than by other mechanisms. There is an additive effect between the benefits of fluoride and molybdenum, though fluoride is undoubtedly the more important. Molybdenum increases the absorption of fluoride from the stomach.
The route by which molybdenum reached individuals living in areas of molybdenum-rich soils was through locally produced and consumed vegetables and especially milk [Anderson, 1969]. Water supplies do not make an important contribution to the daily intake of molybdenum [Hadjimarkos, 1966]. The effect of molybdenum and other trace elements on the development of dental caries in experimental animals has been studied [Navia, 1970; Bertrand et al., 1972; Helsby, 1973]. Molybdenum and also vanadium and strontium were mildly cariostatic. There are indications that ammonium molybdate, (NH4)2MoO4, is cariostatic but that ammonium heptamolybdate, (NH4)6Mo7O24.4H2O, is not [Jenkins, 1967]. The enamel of rat teeth formed in the presence of molybdenum and fluoride has been examined by electron microscopy [Kruger, 1969]. Both elements influence mineralisation. The cariostatic effect of molybdenum is well established and there is need for more research, especially on the mechanism of its action, the level required, and the method of administration.
Hadjimarkos, 1966; Anderson, 1969; Jenkins, 1967; Lossee and Adkins, 1971].
Navia, J. M., Advan. Chem. Ser., 1970, 94, 123.
Bertrand, G., Blanquet, P. and Laparra, J. C. R. Soc. Biol., 1972, 166, 353.
Helsby, C. A., Caries Res., 1973, 7, 332.
Jenkins, G., British Dental Journal, 1967, 435, 500, 545.
Kruger, B. J., J. Dent. Res., 1969, 48, 1303.
Effect of molybdenum on the immunological reactivity of organisms
The addition of molybdenum as an aqueous solution of ammonium molybdate in amounts of 50-250 mg/kg to the diet of rabbits daily for up to 12 months increased the immunological reaction towards Bact. proteus OX19 culture. The optimum dose was 250 mg/kg when the amount of antibodies and phagocytes was two to three times higher than in control animals [Devyatka et al., 1971].
Devyatka, D. G., Val'chuk, N. K., Voronina, T. Z. and Bukhovets, V. J., Gig. Sanit., 1971, 36, 104.
Molybdenum and cancer
For a review see
Metal passivity as mechanism of metal carcinogenesis: Chromium, nickel, iron, copper, cobalt, platinum, molybdenum, CORNELIA RICHARDSON-BOEDLER Toxicological & Environmental Chemistry, Jan–Mar 2007; 89(1): 15–70.
There are indications of a relationship between molybdenum deficiency and the development of various tumours. The incidence of oesophageal cancer in areas of South Africa varies depending on location [Davies, 1975; Rose, 1968; Burrell et al., 1966]. The gardens of a group of Bantu women who died of cancer were less fertile and less productive than those of tumour-free women. Severe signs of molybdenum deficiency were noted in plants grown in gardens of the cancer sufferers. It is suggested that the molybdenum deficiency resulted in the plants being more prone to attack by fungi, e.g. Aspergillus flavus, which has been implicated as a cause of liver cancer in animals. The distribution of molybdenum in mouse liver and Sarcoma 180 was determined following the intraperitoneal injection daily for 6 d of various molybdenum compounds [Caruthers and Regelson, 1963]. With Na4SiMol2O40, MoCl5, and MoBr2 there was an accumulation of molybdenum in the liver and the tumour but with (NH4)6Mo7O24.4H2O and Mo3(H2C2O4).2H2O there was no such accumulation. The copper and zinc contents of the liver and the tumour were not affected by any of the molybdenum compounds nor was the growth rate of the tumour. It is possibly relevant that the concentration of xanthine oxidase is relatively low in various tumours and that tumour growth in mice was decreased by treatment with xanthine oxidase concentrates [Bray, 1963].
Davies, I. J. T., Intake (British Medical Journal. Advertiser's Supplement), 1975, 39, 4.
Rose, E. F., Cancer Research, 1968, 28, 2390.
Burrell, R. J. W., Roach, W. A. and Shadwell, A., J. Nat. Cancer Inst., 1966, 36, 201, 211.
Caruthers C.and Regelson, W.,Oncologia, 1963, 16, 101.
Bray, R. C., in The Enzymes, ed. Boyer, P. D., Hardy, L. and Myrback, K., Academic Press, New York, 2nd Edn., 1963, 7, 533.
Two randomised nutrition intervention trials were conducted in Linxian, an area of north central China with some of the world's highest rates of oesophageal and stomach cancer and a population with a chronically low intake of several nutrients. to assess the effects in nearly 30 000 participants of daily supplementation with: retinol and zinc; riboflavin and niacin; vitamin C and molybdenum; and beta-carotene, alpha-tocopherol, and selenium. The second trial provided daily multiple vitamin-mineral supplementation; or placebo in 3318 persons with oesophageal dysplasia, a precursor to oesophageal cancer. After supplements were given for 5.25 y in the general population trial, small but significant reductions in total relative risk [(RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium but not the other nutrients. The largest reductions were for cerebrovascular disease mortality, but the effects differed by sex: a significant reduction was observed in men (RR = 0.45) but not women (RR = 0.90).Restoring adequate intake of certain nutrients may help to lower the risk of cancer and other diseases in this high-risk population [Blot et al., 1995].
Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W.D., Dawsey, S.M., Li, B.,. The Linxian Trials - Mortality-Rates By Vitamin-Mineral Intervention Group, American Journal Of Clinical Nutrition,1995, 62, S1424-S1426.
Xanthine dehydrogenase (EC 1.1.1.204) is a molybdenum iron-sulfur, flavin hydroxylase involved in purine catabolism. Xanthine dehydrogenase-induces activation of bioreductive agents including chemotherapeutic agents requiring bioreductive activation for their antineoplastic activities. Xanthine dehydrogenase is potentially important as an enzyme targeted in chemotherapeutic regimens is discussed [Pritsos et al., 1994].
Pritsos, C.A., Gustafson, D.l., Xanthine Dehydrogenase And Its Role In Cancer-Chemotherapy, Oncology Research, 1994, 6, 477-481.
The antitumor active molybdocene dichloride Cp2MoCl2 formed two stable adducts at pD 6 which were tentatively assigned as a Cp2Mo-glutathione chelate involving coordination of the cysteine thiol and glycine carboxylate to the molybdenum centre, and a thiol centred 1:2 Cp2Mo-glutathione complex. The implications for the mechanism of antitumor action of the metallocene dihalides are discussed.
Mokdsi, G. and Harding, M. M., A H-1 NMR study of the interaction of antitumor metallocenes with glutathione, Journal of Inorganic Biochemistry, 2001, 86, 611-616.
Interest in the aqueous, bio-organometallic chemistry of metallocene dihalides has stemmed from the potent antitumor properties of titanocene dichloride, including results from human clinical trials. Key results on the biological chemistry of molybdocene dichloride are reviewed. Under physiological conditions the positively charged monoaquated species Cp2Mo(OH)(OH2)+, in equilibrium with the dipositively charged dimer Cp2Mo(mu-OH)2MoCp2, is present.Studies of the coordination chemistry of Cp2MoCl2 with nucleobases, nucleotides, single-stranded and double-stranded oligonucleotides, and calf-thymus DNA have shown that, while simultaneous phosphate(O) and heterocyclic(N) adducts are formed with nucleotides, negligible interaction with DNA occurs under physiological conditions. Cp2MoCl2 forms strong, non-labile complexes with deprotonated thiols in amino acids. Molybdocene dichloride is able to catalyse the hydrolysis of activated phosphate esters under physiological conditions, but hydrolysis of unactivated phosphodiesters is only significant at pH 4. Limited antitumor activity results, inhibition studies with protein kinase C and topoisomerase II, structure-activity and cell-uptake studies have provided some insight into possible mechanisms of antitumor action.
Waern, J.B. and Harding, M. M., Bioorganometallic chemistry of molybdocene dichloride, Journal of Organometallic Chemistry, 2004, 689, 4655-4668.
The compounds molybdenocene dichloride (Cp2MoCl2) and [Cp2Mo(L)(n)]Cl2 (n = 1, L = 6-mercaptopurine, 6- mercaptopurineribose, 2-amine-6-mercaptopurine and 2-amine-6- mercaptopurineribose and n = 2, L = D-penicillamine) have antitumour properties. Their complexes with calfthymus DNA have been investigated by cyclic voltammetry. (Cp2MoCl2) and [Cp2Mo(L)(n)]Cl2 (n = 1, L = 2-amine-6- mercaptopurine and 2-amine-6-mercaptopurineribose and n = 2, L = D-penicillamine) complexes showed weak DNA bindings (3.2- 10.1%) while the complexes containing the ligands 6- mercaptopurine and 6-mercaptopurineribose showed negligible interactions.
Rodriguez, M.I., Chavez-Gil, T., Colon, Y., Diaz, N., and Melendez, E., Molybdenocene-DNA interaction studies using electrochemical analysis, Journal of Electroanalytical Chemistry, 2005, 576, 315-322.
Mo and cancer molybdenocene
In the range 4 <=, pD <=, 9 by NMR spectroscopy the ribonucleosides and ribonucleoside monophosphates uridine, adenosine, cytidine, guanosine, 5'-UMP, 5'-AMP, 5'-CMP and 5'-GMP bind Cp2Mo2+ exclusively through the ribose moiety giving rise to the chelate complexes [Cp2Mo(urd-O2',O3')], [Cp2Mo(ade-O2',O3')], [Cp2Mo(cyd-O2',O3')], and [Cp2Mo(gua-O2',O3')]. The ribonucleotides form three types of complex with Cp2Mo2+ in neutral solution, namely N,PO-macrochelates, PO,O3'-coordinated species as well as O2',O3'-chelates, while at pD 9 only sugar coordination is observed.
Erxleben, A. and Yovkova, L., Reaction behavior of molybdocene dichloride towards ribonucleosides and ribonucleoside monophosphates: Rare example of sugar coordination, Inorganica Chimica Acta, 2006, 359, 2350-2360.
Waern, J.B., Harris, H. H., Lai, B., Cai, Z. H., Harding, M. M., and Dillon, C. T., Intracellular mapping of the distribution of metals derived from the antitumor metallocenes, Journal of Biological Inorganic Chemistry, 2005, 10, 443-452.
Molybdocene is cytotoxic
In V79 Chinese hamster lung cells Cp2MoCl2 produced significant genotoxic damage: 0.2 micronuclei/1000 binucleated cells were induced per mu M of Cp2MoCl2. Distinct morphological alterations of the nuclei, condensation of chromatin, and a high incidence of polynucleated cells were observed. Implications for the mechanism of antitumor action of molybdocene dichloride are discussed. (c)
Campbell, K. S., Foster, A. J., Dillon, C. T., and Harding, M. M., Genotoxicity and transmission electron microscopy studies of molybdocene dichloride, Journal of Inorganic Biochemistry, 2006, 100, 1194-1198.
Anti-cancer activity of molybdophosphate: heteropoly Mo
The review includes a useful account of the biochemical activity of molybdenum heteropoly compounds, specifically 12-molybdophosphoric acid, and applications as biomedical agents: antitumoral, anticoagulant, antibacterial, antiviral activity. The antitumour activity of molybdophosphoric acid in in vitro tests on human cervix carcinoma cells was low and less than the activity of tungstophosphoric acid. Molybdophosphoric acid did not damage red blood cells. Molybdophosphoric caused a slight increase of the coagulation time of human blood plasma (49 s compared with 40 s) but less than tungstophosphoric acid (100 s). The polyoxometallates did not exhibit antibacterial activity or antiviral activity on plant viruses.
Mioc, U. B., Todorovic, M. R., Davidovic, A., Colomban, P., and Holclajtner-Antunovic, I., Heteropoly compounds - From proton conductors to biomedical agents, Solid State Ionics, 2005, 176, 3005-3017.
Polyoxomolybdate
The polyoxomolybdate hexabis(isopropylammonium) heptamolybdate trihydrate, [NH3Pri]6[Mo7O24].3H2O (PM-8) suppressed the growth of Co-4 human colon cancer, MX-I human breast cancer and OAT human lung cancer xenografted in nude mice. In an MTS assay DNA ladder formation and detection of apoptotic bodies in nuclei showed that antitumor activity of PM-8 in MKN45 cells was due to apoptosis [programmed cell death]. PM-8 shows promise as a novel anti-cancer agent.
Mitsui, S., Ogata, A., Yanagie, H., Kasano, H., Hisa, T., Yamase, T., and Eriguchi, M., Antitumor activity of polyoxomolybdate, [NH3Pri]6[Mo7O24].3H2O, against, human gastric cancer model, Biomedicine & Pharmacotherapy, 2006, 60, 353-358.
See also
Oda, M., Inoue, M., Hino, K., Nakamura, Y., and Yamase, T., Enhancement effect of polyoxometalates on NGF-induced neurite-outgrowth of PC12 cells, Biological & Pharmaceutical Bulletin, 2007, 30, 787-790.
2,5-dihydroxybenzoate molybdenum(VI) complex
2,5-dihydroxybenzoate molybdenum(VI) complex may provide a valuable tool in cancer chemotherapy
Thomadaki, H., Karaliota, A., Litos, C., and Scorilas, A., Enhanced antileukemic activity of the novel complex 2,5-dihydroxybenzoate molybdenum(VI) against 2,5-dihydroxybenzoate, polyoxometalate of Mo(VI), and tetraphenylphosphonium in the human HL-60 and K562 leukemic cell lines, Journal of Medicinal Chemistry, 2007, 50, 1316-1321.
Molybdenum and cancer ― polyoxomolybdate anti-tumour activity
The polyoxomolybdate(V) [Me3NH]6[(H2MoV12O28)(OH)12(MoVIO3)4].2H2O] (abbreviated PM-17), is prepared by photo-reduction of the heptamolybdate, [NH3Pri]6[MoVI7O24].3H2O (PM-8). It is an anti-tumour agent inhibiting the growth of human pancreatic cancer (AsPC-1) xenografts in a nude mice model, and induced morphological alterations in tumour cells. Correspondingly, PM-17 repressed the proliferation of AsPC-1 cells and human gastric cancer cells (MKN45) depending on the dose in vitro.
It is proposed that PM-8 could be taken preferentially into tumour cells and reduced biologically probably in the mitochondrial system. PM-17 is one of the reduced species of PM-8. The effect of the biological reduction would be to inhibit ATP generation. The reduction product is ca ten-fold more toxic than PM-8. Such a difference in toxicity between PM-8 and its reduced species would lead to a tumour-selective inhibition because (a) the reduced species, on account of its greater molecular weight, would stay longer in the tumour cells (b) the tumour cells exhibit a higher metabolism.
Doses of PM-17 (125 microg and 500 microg per 100 microL 0.9% NaCl solution, per body per day) reduced the growth rate, compared with a control, of AsPC-1 tumour cells implanted in mice over a period of 40 d without affecting the growth rate of the mice. The tumour growth inhibition was greater with the higher PM-17 doses (33.5% and 68.3% after 41 days). Thus PM-17 inhibits the proliferation of AsPC-1 human pancreatic tumours in a dose-dependent manner in vivo.
An account of the possible mechanism of tumour cell death is given. PM-17 induces both apoptosis and autophagy in human pancreatic cancer AsPC-1 cells.
Sharp DNA laddering was observed after treatment with PM-17 by agarose gel electrophoresis of cell DNA extracts which fonfirmed the induction of apottosis by PM-17.
PM-17 was not toxic to mice; they showed no impaired renal or hepatic function, nor haematocytes nor less of body weight.
[Apoptosis: a form of programmed cell death in multicellular organisms from Greek: apo - from, ptosis – falling (http://en.wikipedia.org/wiki/Apoptosis). An active process requiring metabolic activity by the dying cell, often characterised by cleavage of the DNA into fragments that give a so called laddering pattern on gels. (http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=apoptosis).
Autophagy: a catabolic process involving the degradation of a cell's own components through the lysosomal machineryGreek roots: auto, self, and phagy, eatinghttp://en.wikipedia.org/wiki/Autophagy.]
Ogata, A., Yanagie, H., Ishikawa, E., Morishita, Y., Mitsui, S., Yamashita, A., Hasumi, K., Takamoto, S., Yamase, T., and Eriguchi, M., Antitumour effect of polyoxomolybdates: induction of apoptotic cell death and autophagy in in vitro and in vivo models, British Journal of Cancer, 2008, 98, 399-409.
Lowering blood glucose and free fatty acid levels
Both Na2MoO4 (used as a control) and cis-MoO2L22 L= maltol (3-hydroxy-2-methyl-4-pyrone) were effective in lowering blood glucose and free fatty acid levels. Diabetic rats treated with molybdate showed significant improvements in postischemic cardiac function.
Lord, S.J., Epstein, N.A., Paddock, R.L., Vogels, C.M., Hennigar, T.L., Zaworotko, M.J., Taylor, N.J., Driedzic, W.R., Broderick, T.L., Westcott, S.A., Synthesis, characterization, and biological relevance of hydroxypyrone and hydroxypyridinone complexes of molybdenum, Canadian Journal Of Chemistry-Revue Canadienne De Chimie, 1999, 77, 7, 1249-1261.
Tetrathiomolybdate and Wilson’s disease
Ammonium tetrathiomolybdate treats chronic Cu poisoning in sheep and is recommended for Wilson's disease in humans (congenital inability to excrete copper resulting in its accumulation) [Haywood et al., 1998]. In the tetrathiomolybdate-treated sheep Mo accumulated in brain, liver, kidney, heart, skeletal muscle, pituitary, adrenals, testes and ovaries and was retained after cessation of treatment, except in liver, kidney and skeletal muscle. Cu increased and was retained in the cerebellum and medulla oblongata in the tetrathiomolybdate-treated high-Cu Cambridge groups. Brain Cu and Mo concentrations showed a strongly positive correlation in the high-Cu Ronaldsay group 7 months after tetrathiomolybdate treatment. Tetrathiomolybdate is not all excreted; Mo is widely distributed and retained in many organs including brain and pituitary. Tetrathiomolybdate may redistribute some displaced excess liver Cu to the brain.
Haywood, S, Dincer, Z, Holding, J, Parry, NM, Metal (molybdenum, copper) accumulation and retention in brain, pituitary and other organs of ammonium tetrathiomolybdate-treated sheep, British Journal Of Nutrition, 1998, 79, 329-331.
The uptake of tetrathiomolybdate by the liver and the removal of copper accumulating in the liver in a form bound to metallothionein by tetrathiomolybdate were studied in Long-Evans cinnamon (LEC) rats, an animal model of Wilson’s disease, in order to develop better treatments for the disease and Cu toxicity [Ogra and Suzuki, 1998]. When the dose of tetrathiomolybdate is low, tetrathiomolybdate forms a complex with Cu that can be effluxed into the bloodstream, and then binds selectively to albumin. When the dose is high, tetrathiomolybdate forms an insoluble complex, that is precipitated in the liver. Tetrathiomolybdate taken up by a cell is immobilized in the cell through the dose-dependent formation of a complex containing Cu, Mo and sulfur, which causes further uptake of tetrathiomolybdate. Tetrathiomolybdate does not remove Cu from ceruloplasmin. Tetrathiomolybdate targets a cell accumulating excess Cu as Cu- metallothionein, and removes Cu selectively without interacting with Cu in Cu-enzymes. Tetrathiomolybdate is taken up by the liver depending on the amount of Cu accumulating in the form of metallothionein, and then Cu is effluxed together with Mo in the form of Cu/tetrathiomolybdate complex into the bloodstream.
Ogra, Y., Suzuki, K.T., Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats, Journal Of Inorganic Biochemistry, 1998, 70, 49-55.
Tetrathiomolybdate removes copper accumulating in the form bound tometallothionein in the livers of Wilson’s disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats). Copper in Cu-containing enzymes such as Cu,Zn-superoxide dismutase in liver and ceruloplasmin in plasma was decreased by thiomolybdate; the Cu is in the plasma as a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in superoxide dismutase and ceruloplasmin were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Hepatotoxicity was observed occasionally in the clinical application of tetrathiomolybdate. The activity of glutamic-pyruvic transaminase in serum increased when Wistar rats were treated with sulfide produced through hydrolytic degradation of tetrathiomolybdate and dithiomolybdate. Hydrolytic degradation was enhanced under acidic conditions. Dithiomolybdate DTM is not appropriate as a therapeutic agent for Wilson’s disease due to its easy hydrolysis and production of sulfide.
Ogra,Y., Komada,Y., Suzuki, K.T., Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper, Journal Of Inorganic Biochemistry, 1999,75, 199-204.
The chemistry, biology and therapeutic uses of the thiometallate anions of molybdenum(VI) have been reviewed.
Laurie, S.H., Thiomolybdates - Simple but very versatile reagents, European Journal of Inorganic Chemistry, 2000, 2443-2450.
Metallothionein-bound copper in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson's disease, was removed with ammonium tetrathiomolybdate injected intravenously. In LEC rats, Cu and Mo were excreted into the bile and blood, and the bile is recognized for the first time as the major route of excretion. In Wistar rats (normal Cu metabolism) most of the Mo was excreted into the urine. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo.
Komatsu, Y., Sadakata, I., Ogra, Y., and Suzuki, K. T., Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats, Chemico-Biological Interactions, 2000, 124, 217-231.
Wilson's disease is caused by the excessive accumulation of Cu. It is caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu. Toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. Copper forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. Tetrathiomolybdate has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats). An appropriate protocol for the chelation therapy is proposed together with the mechanisms underlying the occurrence of side-effects
Suzuki, K.T. and Ogura, Y., Biological regulation of copper and selective removal of copper: Therapy for Wilson disease and its molecular mechanism, Yakugaku Zasshi-Journal of the Pharmaceutical Society of Japan, 2000, 120, 899-908.
George, G.N., Pickering, I. J., Harris, H. H., Gailer, J., Klein, D., Lichtmannegger, J., and Summer, K. H., Tetrathiomolybdate causes formation of hepatic copper- molybdenum clusters in an animal model of Wilson's disease, Journal of the American Chemical Society, 2003, 125, 1704-1705.
Ammonium tetrathiomolybdate in treating copper poisoning and Wilson’s disease
Ammonium tetrathiomolybdate (TTM) is an effective treatment for chronic copper poisoning in sheep; it has also been proposed for the treatment of Wilson’s disease in humans. The long-term effects of TTM on five copper-poisoned sheep are reported. The copper-poisoned sheep, after apparently successful treatment with TTM, became infertile and progressively unthrifty and eventually died 2-3 years after treatment. In the TTM treated sheep there was minimal liver damage and no thyroid changes. There was no evidence of neuronal damage in any region of the brain. There were regressive pathological changes of the testes or ovaries, the adrenal glands and the pituitaries associated with the elevated levels of molybdenum. Excess of molybdenum was found in the pituitaries, the adrenals and the brains of affected sheep. Evidently molybdenum introduced systemically as TTM was retained within the brain, pituitary and adrenal glands and so was associated with a toxic endocrinopathy. It is postulated that molybdenum administered as thiomolybdate adversely affects the hypothalamo-adrenohypophyseal system by interfering with trophic hormone release, leading to the cessation of reproductive activity and ultimately the failure of intermediary metabolism. It was proposed that thiomolybdate, directly or indirectly, inhibits the enzyme peptidylglycine á-amidating mono-oxygenase (PAM), an enzyme crucial for the bioactivation of many peptide hormones, including neuropeptides, and a key enzyme in the correct functioning of the neuroendocrine system. PAM is a copper-dependent enzyme. It is found in high concentration in the hypothalamus. Tetrathiomolybdate, in binding to copper in the pituitary or hypothalamus, would make copper unavailable for PAM and thereby inhibit its activity.