Common Toxic Mechanisms and Sites of Action

Enzyme Inhibition/Activation. A major site of toxic action for metals is interaction with enzymes, resulting in either enzyme inhibition or activation. Two mechanisms are of particular importance inhibition may occur as a result of interaction between the metal and sulfhydryl (SH) groups on the enzyme, or the metal may displace an essential metal cofactor of the enzyme. For example, lead may displace zinc in the zinc-dependent enzyme 5-aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme-containing enzymes, such as cytochromes. 

Subcellular Organelles. Toxic metals may disrupt the structure and function of a number of organelles. For example, enzymes associated with the endoplasmic reticulum may be inhibited, metals may be accumulated in the lysosomes, respiratory enzymes in the mitochondria may be inhibited, and metal inclusion bodies may be formed in the nucleus. 

Carcinogenicity. A number of metals have been shown to be carcinogenic in humans or animals. Arsenic, certain chromium compounds, and nickel are known human carcinogens beryllium, cadmium, and cisplatin are probable human carcinogens. The carcinogenic action, in some cases, is thought to result from the interaction of the metallic ions with DNA (see Chapter 11 for a detailed discussion of carcinogenesis). 

Kidney. Because the kidney is the main excretory organ of the body, it is a common target organ for metal toxicity. Cadmium and mercury, in particular, are potent nephro-toxicants and are discussed more fully in the following sections and in Chapter 15. 

Nervous System. The nervous system is also a common target of toxic metals particularly, organic metal compounds (see Chapter 16). For example, methylmercury, because it is lipid soluble, readily crosses the blood-brain barrier and enters the nervous system. By contrast, inorganic mercury compounds, which are more water soluble, are less likely to enter the nervous system and are primarily nephrotoxicants. Likewise organic lead compounds are mainly neurotoxicants, whereas the first site of inorganic lead is enzyme inhibition (e.g., enzymes involved in heme synthesis). 

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