tetrathiomolybdate and dithiomolybdic-acid

Tetrathiomolybdate (TTM) can be used as a specific chelator to remove copper (Cu) accumulating in the form bound to metallothionein (MT) in the livers of Wilson disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats). However, an adverse effect, hepatotoxicity, was observed occasionally on its clinical application. The mechanism underlying the adverse effect of TTM has been studied in comparison with dithiomolybdate (DTM), and a safer and more effective therapy by TTM was proposed based on the mechanism. The activity of glutamic-pyruvic transaminase (GPT) in serum was shown to increase significantly on the treatment of Wistar rats with sulfide produced through hydrolytic degradation of TTM and DTM, the latter being more easily degraded. The hydrolytic degradation of TTM was enhanced under acidic conditions. Cu in Cu-containing enzymes such as Cu,Zn-superoxide dismutase (SOD) in liver and ceruloplasmin (Cp) in plasma was decreased by excessive thiomolybdates, the Cu being found in the plasma in the form of a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in SOD and Cp were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Although both TTM and DTM remove Cu from MT, DTM is not appropriate as a therapeutic agent for Wilson disease due to its easy hydrolysis and production of sulfide.

Topics: Animals; Ceruloplasmin; Chelating Agents; Copper; Drug Stability; Hepatolenticular Degeneration; Humans; Liver; Molybdenum; Rats; Rats, Long-Evans

Four horses were stabled and fed a diet of hay ad libitum, and 2 kg oats per animal per day, for a month. The basic diet was then supplemented with molybdenum, at a rate of 20 mg/kg dry matter for 4.5 months. For one month of this period the diet was supplemented also with sulphur at a rate of 1.2 g/kg dry matter. Analyses of jugular blood samples, obtained at intervals varying between two and 20 days, showed no evidence of a decline in total plasma copper or of an increased proportion of trichloroacetic acid (TCA) insoluble copper in plasma over this period. In separate studies, two other horses were given 99molybdenum (molybdate, 20 to 28 mg Mo, 4 mCi per animal) per os, initially while being fed the basic diet and later while maintained on the molybdenum supplemented diet. 99Molybdenum appeared rapidly in plasma, but the radioactivity was then quickly cleared (half-life 7 to 10 h). The 99molybdenum present was identified as (99Mo)-molybdate. There was no evidence of the persistent, protein-bound (99Mo)thiomolybdates which appear in ruminants. These studies indicate that increased dietary molybdenum is unlikely to interfere with copper metabolism in horses.

Topics: Administration, Oral; Animals; Copper; Diet; Female; Horses; Molybdenum; Pregnancy; Sulfur

The synthesis and purification of the sodium salts of di (MoO2S2(2-)), tri (MoOS3(2-)) and tetra (MoOS4(2-)) thiomolybdate is reported. All three compounds were reversible inhibitors of the ovine ceruloplasmin (Cp) catalysed oxidation of O-dianisidine. Na2MoO2S2 inhibited via a non-competitive mechanism whereas Na2MoOS3 showed mixed non competitive and Na2MoS4 competitive mechanisms. All showed upward curving slope replots. Molybdenum trisulfide (MoS3) was synthesized and displayed mixed type inhibition kinetics but with a linear slope replot. Preliminary evidence suggested that both MoOS3(2-) and MoS4(2-) may also be substrates for ovine Cp.

Topics: Animals; Ceruloplasmin; Kinetics; Molybdenum; Sheep

[99Mo]di-, tri-, and tetrathiomolybdate (5.4 to 62.5 mg of Mo) were given by intravenous injection to sheep maintained on a sulfur-supplemented (3 g of S/kg) diet. All the compounds were metabolized very rapidly over the first 15 min postinjection, but relatively slowly thereafter, with a t1/2 of about 30 hr for dithiomolybdate and 40 h for tri- and tetrathiomolybdate. The [99Mo] metabolites present in plasma were identified by Sephadex G-25 chromatography. The main fate of the compounds injected appeared to be stepwise transformation to molybdate and subsequent rapid urinary elimination. Over 90-100 hr more than 90% of the radioactivity was excreted in urine, compared to less than 5% in the feces. The trichloroacetic acid (TCA) solubility of plasma copper and the diamine oxidase activity of ceruloplasmin was depressed, particularly over the first 15 min postinjection and a more persistant TCA-insoluble Cu fraction was apparent.

Topics: Animals; Edetic Acid; Injections, Intravenous; Male; Molybdenum; Oxidation-Reduction; Radioisotopes; Sheep; Time Factors

When 4 groups of 3 lambs were reared on a milk substitute containing 10.5 mg of Cu per kg DM with or without supplements of Cu, 5 mg, and Mo, 3 mg per kg DM in a 2 X 2 factorial design, Mo, given as ammonium tetrathiomolybdate (MoS4) reduced hepatic Cu retention by one-third but had no effect on the amount or distribution of Cu in plasma or on plasma Mo concentrations. When 2 groups of 5 lambs were weaned on to a cereal-based diet containing 3.5 mg Cu per kg DM and one was given MoS4 in the amount used previously, concentrations of Mo and TCA-insoluble Cu in plasma and the rate of depletion of liver Cu were increased. When Cu, 12 mg per kg DM, was finally added to both diets the plasma changes were reversed but the hepatic retention of Cu was still reduced. In a second experiment, 6 groups of 5 hypocupraemic ewes were repleted with a dietary Cu supplement in the presence of one of 3 Mo sources, molybdate (MoO4), dithiomolybdate (MoO2S2) or tetrathiomolybdate (MoS4) providing 3.0 mg Mo per kg DM each in the presence of low or high dietary S. The effects of the S supplement were dominant, causing the MoO4 and MoO2S2 to behave like MoS4 in impairing Cu and Mo absorption and inducing TCA-insoluble Mo and Cu to accumulate in the plasma: S enhanced these responses to MoS4 even further. On the low S diet, the responses to MoO4 and MoO2S2 were similar but small. It is concluded that at high dietary Mo and S concentrations, sufficient MoS4 forms in the rumen and enters complexes with Cu to impair Cu absorption but that the formation of MoO2S2 does not play an important role in the Cu and Mo antagonism.

Topics: Absorption; Animals; Copper; Feces; Growth; Kidney; Liver; Molybdenum; Sheep

1. Protein-bound, trichloracetic acid- (TCA) insoluble 99Mo appeared in plasma a few hours after the introduction of 99Mo-labelled molybdate (30 mg Mo) into the rumen of sheep maintained on a basic diet supplemented with elemental sulphur (3 g S/d). 2. Most of the 99Mo could be displaced from its protein carrier in vitro and the labelled compounds displaced were identified by sephadex G-25 chromatography as di- and trithiomolybdate. Tetrathiomolybdate was not detected. 3. In control experiments protein-bound, TCA-insoluble 99Mo predominated in plasma after the direct administration of [99Mo]tetrathiomolybdate, either into the rumen or intravenously. The 99Mo could be displaced in vitro and [99Mo]tetrathiomolybdate identified, although [99Mo]trithiomolybdate was also present. The study provides direct evidence of thiomolybdate synthesis and absorption in ruminants in vivo.

Topics: Animals; Chromatography, Gel; Intestinal Absorption; Male; Molybdenum; Protein Binding; Radioisotopes; Rumen; Sheep; Time Factors