Common Toxic Mechanisms and Sites of Action

 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 co factor of the enzyme. For example, lead may displace zinc in the zinc - dependent enzyme δ - aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme - containing enzymes, such as the various cytochromes.

Sub cellular 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 in animals. Arsenic, certain chromium compounds, and nickel are known human carcinogens; beryllium, cadmium, and cisplatin are probable human car cinogens. The carcinogenic action, in some cases, is thought to result from the interaction of the metallic ions with DNA.

Kidney

 Because the kidney is the main excretory organ of the body, it is a common target organ for metal toxicity.

Nervous System

The nervous system is also a common target of toxic metals, particularly organic metal compound. For example, methyl mercury, 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).

Endocrine and Reproductive Effects

Because the male and female reproductive organs are under complex neuroendocrine and hormonal control, any toxicant that alters any of these processes can affect the reproductive system. In addition, metals can act directly on the sex organs. Cadmium is known to produce testicular injury after acute exposure, and lead accumulation in the testes is associated with testicular degeneration, inhibition of spermatogenesis, and Leydig cell atrophy.

Respiratory System

Occupational exposure to metals in the form of metal dust makes the respiratory system a likely target. Acute exposure may cause irritations and inflammation of the respiratory tract, whereas chronic exposure may result in fibrosis (aluminum) or carcinogenesis (arsenic, chromium, nickel).

Metal - Binding Proteins 

The toxicity of many metals such as cadmium, lead, and mercury depends on their transport and intracellular bioavailabiltiy. This availability is regulated to a degree by high affinity binding to certain cytosolic proteins. Such ligands usually possess numerous SH binding sites that can ou compete other intracellular proteins and thus mediate intracellular metal bio availability and toxicity. These intracellular “ sinks ” are capable of partially sequestering toxic metals away from sensitive organelles or proteins until their binding capacity is exceeded by the dose of the metal. Metallothionein (MT) is a low molecular weight metal - binding protein that particularly important in regulating the intracellular bio availability of cadmium, copper, mercury, silver, and zinc. For example, in vivo exposure to cadmium results in the transport of cadmium in the blood by various high molecular weight proteins and uptake by the liver, followed by hepatic induction of MT. Subsequently, cadmium can be found in the circulatory system bound to MT as the cadmium - metallothionein complex (CdMT).