Cadmium protein-bound

Cadmium is effectively accumulated in the kidneys. When the cadmium concentration exceeds 200 gg/g in the kidney cortex, tubular damage will occur in 10% of the population, and proteins begin to leak into urine (proteinuria). When the concentration of cadmium in the kidney cortex exceeds 300 pg/g, the effect is seen in 50% of the exposed population. Typically, excretion of low-molecular weight proteins, such as beta-microglobulin, is increased, due to dysfunction of proximal tubular cells of the kidney. The existence of albumin or other high-molecular weight proteins in the urine indicates that a glomerular injury has also taken place. The excretion of protein-bound cadmium will also be increased. 

The lethal effects of cadmium are thought to be caused by free cadmium ions, that is, cadmium not bound to metallothioneins or other proteins. Free cadmium ions may inactivate various metal-dependent enzymes however, cadmium not bound to metallothionein may have the capacity to directly damage renal tubular membranes during uptake (USPHS 1993). 

Cadmium is bound to proteins and red blood cells in blood and transported in this form, but 50% to 75% of the body burden is located in the liver and kidneys. The half-life of cadmium in the body is between 7 and 30 years, and it is excreted through the kidneys, particularly after they become damaged. 

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. 

Lange-Hesse, K., Dunemann, L. and Schwedt, G. (1991) Development of a combined ultra- and diafiltration technique for use in speciation analysis of protein-bound cadmium in plants. Fresenius J. Anal. Chem., 339, 240-244. 

Szpunar, J., Chassaigne, H., Donard, O.F.X., Bettmer,J. and Lobinski, R. (1997) Specia-tion of protein-bound cadmium in biological materials by size-exclusion and reversed-phase HPLC with ICP-MC detection. Spec. Publ. — Roy. Soc. Client., 202, 131-144. 

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... 

The main routes for cadmium to enter an organism are through the respiratory and digestive tracts. Cadmium is a cumulative poison 5-6% of the total cadmium intake through the digestive tract is absorbed while the rest is eliminated in faeces. About 90% of resorbed cadmium is bound to particular proteins (metallothionein) and deposited in liver, kidneys, bones and spleen (Lehman and Poisner, 1984). Excretion of cadmium is a very slow process and amounts to 0.01% of daily body deposit, and its biological half-life is 10-30 years. 

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. 

When various Au/Cd ratios were employed, the results indicated a dramatic difference between the reactivities of protein-bound zinc and cadmium. Chromatograms for 2/1 and 5/1 ratios are presented in Figure 7 and data for these and other stoichiometries are summarized in Table II. Clearly the zinc is preferentially displaced by gold, in a reaction which goes to completion and is limited by the amount of gold present at the concentrations employed. However, when the zinc is completely displaced, an equilibrium displacement of cadmium is observed, and a decreasing proportion of the gold is MT bound. The chemistry can be represented as follows ... 

Thus with a 2/1 Au/Cd ratio, all the gold is protein-bound and 78% of the zinc, but no cadmium was displaced. At 3/1 and higher ratios, all of the zinc and progressively more cadmium are displaced from the protein. Even with a large excess of Na AuTM, complete displacement of cadmium was not observed (Table 2). 

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

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.)... 

Most terrestrial invertebrates have limited access to water and feed on solid matter. As a consequence, they take up most of their nutrients by ingestion of foodstuffs that are also the vehicle for ingestion of contaminants. Many of the class a , metals that are taken up are found in membrane-bound granules in the cells of the hepatopancreas, although uncertainties remain as to the initiation of granule formation. Other metals, such as the class b metal cadmium, may be in the granule or may be bound to a metallothionein type protein. 

---