tetrathiomolybdate and Hemolysis

Histological, ultrastructural and kidney function techniques were used to assess changes in the kidney of sheep given either copper (Cu) or Cu and the Cu complexing agent thiomolybdate (TM), or TM alone. Kidney function was normal in sheep given Cu and TM together or TM alone. In these animals the cells lining cortical tubules accumulated Cu within numerous, large, electron-dense lysosomes. Sheep given Cu alone developed haemolysis, impaired kidney function and a variety of morphological defects including an increase in number of large lysosomes in cells of the cortical tubules. There was a breakdown of the glomerular endothelial lining and fusion of foot processes. Cells of the cortical tubules showed degeneration and necrosis and an increase in microbodies and rough endoplasmic reticulum. Cortical and medullary blood vessels were dilated, with evidence of breakdown of the endothelial lining. Copper appeared to injure kidney tissue at three sites, tubular epithelium, glomerular basal lamina and capillary blood vessels. Changes reported here are similar to the renal lesions in cadmium toxicity.

Topics: Animals; Copper; Female; Hemolysis; Kidney; L-Iditol 2-Dehydrogenase; Microscopy, Electron; Molybdenum; Sheep; Sheep Diseases; Trace Elements

The distribution of elements in the cells of the liver and kidney of normal sheep, of sheep chronically intoxicated with copper and in sheep given copper and thiomolybdate was studied by atomic absorption spectrophotometry, electron microscopy and electronprobe X-ray microanalysis. Copper concentrations were increased in the liver and kidney during the pre-haemolytic and haemolytic stages of the disease. In addition iron concentrations were markedly increased in the kidney during haemolysis. Copper and molybdenum concentrations were increased in the kidney of sheep receiving copper and thiomolybdate or thiomolybdate alone. By electronprobe X-ray microanalysis at the pre-haemolytic and haemolytic stages, copper together with small amounts of calcium and chromium were found in lysosomes of liver cells. In addition, in animals killed during haemolysis, high concentrations of iron were found in apical lysosomes of kidney proximal tubule cells. Copper and molybdenum were found in apical lysosomes of kidney tubule cells in animals given copper and thiomolybdate or thiomolybdate alone. The accumulation of copper with molybdenum and sulphur in the lysosomes of thiomolybdate treated copper intoxicated animals was demonstrated for the first time and may indicate the sequestration within lysosomes of a copper-molybdenum-protein complex.

Topics: Animals; Copper; Copper Sulfate; Electron Probe Microanalysis; Female; Hemolysis; Iron; Kidney; Liver; Male; Microscopy, Electron; Molybdenum; Organoids; Sheep; Sheep Diseases; Spectrophotometry, Atomic; Trace Elements

1. Twenty-six sheep were used in experiments designed to test the effectiveness of ammonium tetrathiomolybdate in the prevention and treatment of chronic copper poisoning. 2. Intravenous injections of 100 mg ammonium tetrathiomolybdate twice weekly (a) prevented the occurrence of haemolytic crisis in sheep repeatedly dosed with copper sulphate and (b) minimized tissue damage and prevented further haemolytic crisis when given to sheep already in haemolysis. 3. Thiomolybdate prevented excessive deposition of Cu in the liver of sheep receiving orally large amounts of Cu and decreased liver Cu levels in sheep that were not given additional Cu. In the latter sheep, 50 mg ammonium tetrathiomolybdate given twice weekly did not produce histologically-detectable tissue damage even though liver and kidneys contained high levels of molybdenum, and kidneys contained elevated levels of Cu. 4. It is concluded that chronic Cu poisoning can be successfully prevented or treated by intravenous injection of appropriate doses of ammonium tetrathiomolybdate.

Topics: Animals; Copper; Hemolysis; Iron; Kidney; Liver; Molybdenum; Sheep; Sheep Diseases; Spleen; Zinc

1. Fourteen sheep were dosed repeatedly with a solution of copper sulphate (2 g/l) in order to induce chronic copper poisoning and four similar undosed animals acted as controls 2. Thiomolybdate (TM) was intravenously administered to all control sheep and to all except two of the test sheep. A variety of biochemical factors were studied before and after injections of TM. 3. The direct-reacting Cu, whole-blood Cu and plasma Cu concentrations were elevated in animals given TM injections and at the "haemolytic crisis" of untreated chronic Cu-poisoned animals. But most of the increased Cu observed on injecting TM was insoluble in trichloroacetic acid (TCA) and did not enter erythrocytes. The results indicate that uptake of Cu by erythrocytes is essential for haemolysis to occur and that for this to happen the Cu must be in a direct reacting, TCA-soluble form. 4. Increased amounts of Cu were excreted in the urine at haemolysis and at commencement of TM injections. High levels of direct-reacting Cu were found in plasma at these times. 5. Marked changes were not found in caeruloplasmin activity, packed cell volume or the osmotic fragility of erythrocytes except at haemolysis. TM injection s did no alter these factors in any of the sheep studied.

Topics: Animals; Ceruloplasmin; Copper; Erythrocytes; Hematocrit; Hemolysis; Molybdenum; Osmotic Fragility; Sheep; Sheep Diseases