Iii toxic effects of metals a two classes of toxic

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III. TOXIC EFFECTS OF METALS A. Two Classes of Toxic Metal Compounds As intimated in the previous section, the presence of excess quantities of an essential metal can be as deleterious as insufficient amounts. This situation can
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III. TOXIC EFFECT OF METALS 509 arise from accidental ingestion of the element or from metabolic disorders lead- ing to the incapacitation of normal biochemical mechanisms that control uptake and distribution phenomena. These possibilities constitute one major class of metal toxicity. The other broad class results from entry of nonessential metals into the cell through food, skin absorption, or respiration. The toxicities asso- ciated with this latter class have received much recent attention because of the public health risks of chemical and radioisotopic environmental pollutants. In this section, we survey examples of both categories, and discuss ways in which bioinorganic chemistry can contribute to the removal of toxic metals and restoration of normal function. One way involves chelation therapy, in which metal-specific chelating agents are administered as drugs to complex and facili- tate excretion of the unwanted excess element. The use of desferrioxamine to treat iron poisoning is one example of this approach. A second role of bioinor- ganic chemistry is to identify fundamental biological mechanisms that regulate metal detoxification, and to apply the principles that emerge to help control the toxic effects of metal ions in the environment. Recent studies of mercury resis- tance and detoxification in bacteria provide an elegant example of the way in which biochemistry and molecular biology can be used to elucidate events at the molecular level. This work, which has uncovered the existence of metallo- regulatory proteins, is described in some detail in Section III.F below. It repre- sents a benchmark by which other investigations into the mechanisms of metal- detoxification phenomena may be evaluated. B. Copper Overload and Wilson's Disease 8 Wilson's disease results from a genetically inherited metabolic defect in which copper can no longer be tolerated at normal levels. The clinical manifestations are liver disease, neurological damage, and brown or green (Kayser-Fleischer) rings in the cornea of the eyes. Patients suffering from Wilson's disease have low levels of the copper-storage protein ceruloplasmin; the gene and gene prod- ucts responsible for the altered metabolism have not yet been identified. Chela- tion therapy, using K 2 Ca(EDTA), the Ca 2 + ion being added to replenish body calcium stores depleted by EDTA coordination, 2,3-dimercaptopropan-I-ol (BAL, British Anti-Lewisite), or d-penicillamine to remove excess copper, causes the symptoms to disappear. The sulfhydryl groups of the latter two compounds presumably effect removal of copper as Cu(I) thiolate complexes. Wilson's dis- ease offers an excellent opportunity for modem methodologies to isolate and clone the gene responsible for this altered Cu metabolism, ultimately providing a rational basis for treatment.
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