Cadmium biological function

Lane, T. and Morel, F., A biological function for cadmium in marine diatoms, Proc Natl Acad Sci USA, 97 (9), 4627-2631, 2000. 

Cadmium occurs naturally as sulfide co-deposited with zinc, copper, and lead sulfides. It is produced as a by-product in above-mentioned metal processing. Similar to lead and mercury, this heavy metal has no known biological functions in living organisms, and accordingly its accumulation in food and water leads to undesirable consequences to biota. Cadmium toxicology is related to dangerous influence to CNS and excretion systems, firstly, on kidney. 

Metallothionein was first discovered in 1957 as a cadmium-binding cysteine-rich protein (481). Since then the metallothionein proteins (MTs) have become a superfamily characterized as low molecular weight (6-7 kDa) and cysteine rich (20 residues) polypeptides. Mammalian MTs can be divided into three subgroups, MT-I, MT-II, and MT-III (482, 483, 491). The biological functions of MTs include the sequestration and dispersal of metal ions, primarily in zinc and copper homeostasis, and regulation of the biosynthesis and activity of zinc metalloproteins. 

Although these cations and anions are indispensable, excessive amounts of them are toxic, so that it is important that their concentrations are regulated, either by mechanisms existing in the animal or by externally imposed controls. There are also several kinds of metal ions found in Nature which do not appear to serve any useful biological function but which are highly toxic if they are absorbed into the body. These include arsenic and the environmental pollutants lead, cadmium and mercury ions. Most of the remaining metals occur as inert species such as the aluminosilicates and titanium dioxide that are poorly absorbed, if at all, by plants and animals, or are present in only trace amounts and have little physiological effect. 

The behavior of metals as atoms or ions deeply affects the electrochemical reactions they undergo, and similarly affects the metabolism of plants and animals. Iron, copper, cobalt, potassium, and sodium are examples of metals that are essential to biological function. Some metals such as cadmium, mercury, lead, barium, chromium, and beryllium are highly toxic. 

Even though MTs exist naturally with zinc and/or copper bound to them, the discovery of the first MT in 1957 from horse kidney was the result of a search for a cadmium protein. Since then, MTs have continuously challenged the interest of chemists and life scientists. A search in the SciFinder database with metallothionein as the entry yields about 15,000 publications and reveals more than 700 articles per year over the 1991-2001 decade. It also shows that developments in MT research have been covered by about 300 reviews. The widespread occurrence of MTs in nature suggests that they serve an important biological function not yet completely established. It would appear that MTs have no enzymatic activity, nor do they perform any catalytic role in known metabolic processes. Precise identification of the function of MTs accounts for the outstanding number of works available (as indicated by the search results) and prompts most of the research currently being undertaken. 

Biological Function and Medical Significance. Until more conclusive evidence is found suggesting cadmium, lead and tin are essential, the description of any possible biological function seems inappropriate. The toxicologic aspects of cadmium, lead and tin are of medical significance. However, a proper discussion of the toxicology of those elements is beyond the scope of this presentation and is adequately done elsewhere (67,68,69). 

The first evidence that cadmium had a beneficial biological function came from growth data in laboratory cultures of the diatom Thalassiosira weissflogii [43,45]. As shown in Fig. 10, cultures of this coastal diatom grow slowly when the unchelated Zn concentration in the medium is reduced to about Zn = 3 pM. pM. These same cultures grow much faster when Cd is added to the medium at unchelated concentrations >5 pM [46]. This effect, which is particularly obvious at low Co concentrations, has now been observed in other families of marine phytoplankton. For example, Cd enhances the growth rate of the cosmopolitan coccolithophore Emiliana huxleyi when the unchelated Zn and Co concentrations in the medium are below 1 pM (Fig. 10) [42]. From similar laboratory studies, it appears that Zn, Cd, and Co can substitute for each other in many marine eukaryotic phytoplankton [47-51]. 

Recent studies revealed that cadmium-based semiconductor nanocrystals did not affect the biological functions if they were completely coated with organic ligands [58, 59]. After the ligands were detached, the nanocrystals became extremely toxic [59]. The detachment of the ligands will not only destabilize the colloidal system but also cause possible cytotoxic problems [56]. 

Some metals, including heavy metals, affect negatively people s health, either individually or forming metal compounds, and therefore they must be controlled. Moreover, there are toxic semi-metaUic elements the so-called metalloids, such as arsenic and selenium, which should also be monitored. Basically, this group of pollutants can be classified in (1) metals and metalloids that are necessary to support life in very small amounts, but toxic in larger amounts, e.g. copper, zinc, chromium, arsenic, or selenium (2) metals with unknown biological function which are extremely toxic even at trace levels, e.g. mercury, cadmium, or lead. 

Cherian MG (1980) Biliary excretion of cadmium in rat. III. Effects of chelation agents and change in intracellular thiol content on biliary transport and tissue distribution of cadmium. J Toxicol Environ Health 6 379-391 Cherian MG, Chan HM (1993) Biological functions of metallothionein. In Suzuki KT, Imura N, Kimura K (eds) Metallothionein III. Birkhauser, Basel, pp 87-109... 

Cadmium and zinc are related transition metals with contrasting biological roles. Zinc is an essential ion (functioning catalytically and structurally in proteins) and probably has a specific transport mechanism for entering all cells, whereas cadmium is a toxic ion with no known biological functions. Cd " needs to be excluded, if possible, or to be extruded when found inside the cell. Because of the chemical similarity between Zn and Cd, it is difficult to exclude cadmium specifically from zinc uptake systems. The cell uses an efflux transporter as the strategy for keeping a low cytoplasmic concentration of cadmium. 

The biochemistry of cadmium is intimately linked to that of MT. The discovery of MT was the result of a search for a biological function of cadmium [14]. The name metallothionein was chosen for this cadmium-binding protein isolated from horse kidneys to indicate the occurrence of several types of metal ions in the isolated... 

The volume terminates with Chapter 16 in which also the essentiality of Cd " for certain diatoms is pointed out. The distribution of Cd " in the ocean is very similar to that of major nutrients suggesting that it may be taken up by marine phytoplankton at the surface and remineralized at depth. At high concentration, Cd is toxic to phytoplankton as it is for many organisms. However, at relatively low concentrations, Cd " can enhance the growth of a number of phytoplankton species under Zn limitation possibly Cd is taken up either by the Mn or the Zn transport system. The otdy known biological function of Cd is to serve as a metal ion cofactor in cadmium-carbonic anhydrase (CDCA) in diatoms. The expression of CDCA is regulated by the availabilities of Cd " and Zn " both Zn " and Cd can be used as the metal ion cofactor and be exchanged for each other in certain marine phytoplankton species. 

Metallothioneins (MT) are unique 7-kDa proteins containing 20 cysteine molecules bounded to seven zinc atoms, which form two clusters with bridging or terminal cysteine thiolates. A main function of MT is to serve as a source for the distribution of zinc in cells, and this function is connected with the MT redox activity, which is responsible for the regulation of binding and release of zinc. It has been shown that the release of zinc is stimulated by MT oxidation in the reaction with glutathione disulfide or other biological disulfides [334]. MT redox properties led to a suggestion that MT may possesses antioxidant activity. The mechanism of MT antioxidant activity is of a special interest in connection with the possible antioxidant effects of zinc. (Zinc can be substituted in MT by some other metals such as copper or cadmium, but Ca MT and Cu MT exhibit manly prooxidant activity.)... 

Toxicity of cadmium increases in cases of zinc deficiency, due to the zinc substitution in biological systems, which leads to functional disorders. Cadmium reduces assimilation of vitamins C and D. However, a large amount of these vitamins in the diet will decrease the toxicity of cadmium through the reduction of its absorption from the intestinal tract (Friberg et ah, 1986 Hill, 1996 McLaughlin et ah, 1999). 

Selenium is readily available in a variety of foods including shrimp, meat, dairy products, and grains, with a recommended daily intake of 55 to 70 jug. It occurs in several forms with Se+6 being biologically most important. Selenium is readily absorbed by the intestine and is widely distributed throughout the tissues of the body, with the highest levels in the liver and kidney. It is active in a variety of cellular functions and interacts with vitamin E. Selenium appears to reduce the toxic effects of metals such as cadmium and mercury and to have anticarcinogenic activity. Selenium produces notable adverse effects both in deficiency and excess thus recommended daily intake for adults is approximately 70 Jg/day but should not exceed 200 pg/day. 

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