Metal-induced pathology

In this section, we discuss the possible mechanisms by which metals may induce cancer. A review of the current literature reveals several common themes with regard to the effects of carcinogenic metals on the cellular level. These include DNA damage, the inhibition of DNA repair, generation of reactive oxygen species, and effects on apoptosis and signal transduction These are not discrete phenomena but, rather, are interrelated in the pathology of metal-induced cancer. 

CD spectroscopy has also provided valuable insight into the chemical stability and chemical denaturation of proteins. A recent study by Rumfeldt etal. examines the guanidinium-chloride induced denaturation of mutant copper-zinc superoxide dismutases (SODs). These mutant forms of the Cu, Zn-SOD enzyme are associated with toxic protein aggregation responsible for the pathology of amyotrophic lateral sclerosis. In this study, CD spectroscopy was used in conjunction with tryptophan fluorescence, enzyme activity, and sedimentation experiments to study the mechanism by which the mutated enzyme undergoes chemical denaturation. The authors found that the mutations in the enzyme structure increased the susceptibihty of the enzyme to form partially unfolded destabilized monomers, rather than the stable metaUated monomer intermediate or native metallated dimer. 

HSPs as cellular markers of stress HSPs are involved in various aspects of cellular function and a lot is being learnt about its role in normal and pathological states. Recent studies from lower animals, especially fish, have revealed the potential use of induced fish HSPs as a biomarker of exposure to environmental stressors. Industrial effluents, polycyclic aromatic hydrocarbons, metals such as copper, zinc, mercury, pesticides, etc. have shown to induce HSP in fish. Further, the HSP response may vary with the stressor, tissue, species of fish, and the family of HSP studied. Hence it appears that a more extensive and probably a high-throughput profiling (using genomic and pro-teomic) approaches may be necessary to identify patterns of HSP modulation by various stressors. 

Fig. 13. Interplay of ROS and RNS in physiology and pathology. When produced at steady-state levels, superoxide is efficiently removed by SODs. Under these conditions, NO reacts mainly hy activating soluble guanylate cyclase to produce cGMP and/or to induce posttransla-tional modification of protein by forming S-nitrosothiols. However, in different pathologies, when one or both of the molecules are overproduced or/and SOD levels reduced, NO and 02 combine to give peroxynitrite, a powerful oxidant. Perox3mitrite can react directly with the biomolecules or can homolytically decompose to give OH and NO2 radicals, both of which can additionally he formed in the reaction of superoxide with free metal ions and in reaction of NO with oxygen, respectively.

The term biochemical lesion was introduced some 35 years ago to crystallize the idea that pathological disturbances in tissues are initiated by changes in their biochemistry (Peters, 1963). As pointed out very early, the toxic agents (metals, arsenoxides, vesicants, narcotics, cyanide, carbon monoxide, antimetabolites, etc.) induce a metabolic defect, a biochemical lesion, before alterations in the structure of cells may be observed. 

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