Metallothionein excretion

For patients who are unable to tolerate penicillamine, trientine, another chelating agent, may be used in a daily dose of 1-1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Zinc acetate administered orally increases the fecal excretion of copper and is sometimes used for maintenance therapy. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. 

Cadmium is a cumulative toxicant with a biologic half-life of up to 30 years in humans. More than 70% of the cadmium in the blood is bound to red blood cells accumulation occurs mainly in the kidney and the liver, where cadmium is bound to metallothionein. In humans the critical target organ after long-term exposure to cadmium is the kidney, with the first detectable symptom of kidney toxicity being an increased excretion of specific proteins. 

Liu JX, Nordberg GF. 1995. Nephrotoxicities of aluminum and/or cadmium-metallothionein in rats Creatinine excretion and metabolism of selected essential metals. Pharmacol Toxicol 77 155-160. 

Endogenous substances other than metallothionein may be involved in minimizing the effects of heavy metals and excreting them from the body. Hepatic (liver) glutathione, discussed as a phase II conjugating agent in Section 7.4, plays a role in the excretion of several metals in bile. These include the essential metals copper and zinc toxic cadmium, mercury(II), and lead(II) ions and organometallic methyl mercury. 

Zinc was known to produce copper deficiency in experimental animals. The first report of zinc treatment for Wilson disease was published in 1979. Zinc causes induction of metallothionein in the intestinal cells, which binds copper with high affinity and holds it with high affinity until the intestinal cells are sloughed off. Thus, zinc inhibits absorption of copper from the intestine and increases the fecal excretion of copper. Zinc also blocks the reabsorption of endogenously secreted copper from sahva and gastric juice. A major advantage of zinc treatment is its low toxicity. 

Copper The daily intake from food is 0.8—2.0 mg it is released into the portal vein via copper-transporting ATPase. The transport of copper, which is toxic in its free form, is effected by the binding to ceruloplasmin, albumin and transcuprin. Copper is bound to reduced glutathione and metallothionein in the hepatocytes and distributed to various organelles or incorporated into enzymes. The biological effects of copper are manifold and essential for some cellular functions, (s. p. 50) Copper is toxic not only in its free form, but also in cases of overload (e. g. cirrhosis in childhood due to the consumption of water from copper pipes). Copper homoe-ostasis is regulated via biliary excretion (normal value about 1.2-2.0 mg/day), so that the normal value in serum is 75-130 fg/dl. (321, 323, 370, 383, 386) (s. p. 102)... 

The urinary excretion of metallothionein parallels urinary Cd and evidences early renal dysfunction as indicated by increased excretion of either p2-microglobu-lin or al-microglobuhn. Based on these results, the urinary excretion of metallothionein reflects not only the level of Cd exposure but also any renal dysfunction caused by long-term Cd exposme [18, 29]. 

Some causal relations among various urinary indices were identified using path analysis method. Cadmium-induced renal dysfunction develops in the following order Cd exposure —> increased p2-microglobulin and/or metallothionein —> increased excretion of amino-nitrogen and/or total protein —> increased excretion of glucose [76]. 

Tohyama C, Shaikh ZA, Nogawa K, Kobayashi E, Honda R. Elevated urinary excretion of metallothionein to environmental cadmium.Toxicology 1981 20 289-297. 

Trace metal disturbances may be due to the uremia per se. Indeed, as the urinary excretion route is an important pathway of elimination of many trace elements, i.e. silicon, strontium, aluminum,... impairment of the kidney will be an important determinant of their accumulation, whilst in the presence of a reabsorptive defect a number of trace elements, especially those that are reabsorbed because of their essential role, be lost resulting in a deficient state. The presence of proteinuria may reasonably result in losses of protein bound elements. It has also been shown also that residual renal funchon may importantly alter the accumulation and hence toxic effects of aluminum [2]. In uremia translocation of a particular metal from one tissue to another may also occur. As an example, under normal circumstances the kidney is an important target organ for cadmium. In chronic renal failure however, possibly as a consequence of a reduction in binding proteins (e.g. metallothionein), the concentrahon of cadmium in this tissue decreases to extremely low levels which... 

Biochemistry of Zinc and Copper Zinc in the -Cells of the Pancreas Absorption of Zinc and Copper Plasma Zinc and Copper Levels Metallothionein and Ceruloplasmin Zinc Excretion and Zinc Deficiency Copper Excretion and Copper Deficiency Genetic Diseases of Copper Metabolism Molybdenum, Sulfite, and Sulfate Molybdenum Molybdenum Biochemistry Sulfite Sulfate... 

If one had to state an overall role of copper in the body, one might say oxygen metabolism. One major factor shared by both zinc and copper is that both metal ions occur bound to metallothionein. The function of metallothionein is not firmly established. Copper is bound to another protein, ceruloplasmin, which occurs in the cell and plasma. The function of this protein is not clear either. Zinc absorption, as iron absorption, is impaired by high levels of phytic acid. Copper absorption is not inhibited by phytic acid. The major route of excretion of both metal ions is fecal, rather than urinary. 

It has been known for some time that Wilson s Disease in inherited as an autosomal recessive trait and that its prevalence in the general population amounts to one in 200,000 ( 82,89,90). The cause for the ceruloplasmin deficiency seems to be attributable to impairment of the lysosomal ability to excrete copper into bile, which is the major excretory route for copper (80,81). Bile pigments are known to be good copper chelators (91). In addition, a copper metallothionein with high binding capacity for copper has been identified in livers of subjects with Wilson s Disease (92) and in human fetal liver (93). 

See also Acetaminophen Acetylaminofluorene Acetyl-salicylic Acid Aflatoxin Biotransformation Blood Bromo-benzene Carbon Tetrachloride Chloroform Dioxins Distribution Ethanol Excretion Immune System Is-oniazid Lipid Peroxidation Metallothionein Peroxisome Proliferators Tissue Repair. 

Up to 30% of ingested zinc is absorbed from the small intestine however, a homeostatic mechanism controls the absorption. Nutritional status also influences zinc absorption deficiency of pyridoxine or tryptophan somewhat inhibits absorption. Zinc induces a zinc metallothionein, the form in which it is bound to the liver and other tissues. The pancreas is high in zinc, and in males the prostate gland contains the greatest store of zinc. Zinc is excreted in the feces. 

Its synthesis in organisms is induced by the above-mentioned metals and is involved in the storage of these metals in organs. Zinc metallothionein can detoxify free radicals. Cadmium-induced metallothionein is able to bind cadmium intracel-lularly and in this way protects the organism against the toxicity of this metal. Cadmium is transported in the plasma as a complex with metallothionein and may be toxic to the kidney when excreted in the glomerular filtrate. 

The physiological role of metallothioneins remains unknown, but it may be, in part, to protect cells from metal toxicity by binding metal ions. Metallothioneins may also be important for intestinal and renal absorption of metals and for metal storage and excretion. 

In another rare inherited disorder, called Wilson s disease, excessive amounts of copper accumulate in liver and brain tissue. A prominent symptom of the disease is the deposition of copper in greenish-brown layers surrounding the cornea, called Kayser-Fleischer rings. Wilson s disease is now known to be caused by a defective ATP-dependent protein that transports copper across cell membranes. Apparently, the copper transport protein is required to incorporate copper into ceruloplasmin and to excrete excess copper. In addition to a low copper diet, Wilson s disease is treated with zinc sulfate and the chelating agent penicillamine (p. 123). Describe how these treatments work. (Hint Metallothionein has a greater affinity for copper than for zinc.)... 

---