MECHANISMS OF ACTION OF TOXICANTS

MECHANISMS OF ACTION OF TOXICANTS

Poison act in small doses, affecting the whole body. Any theory which employs merely chemical terms and analogous in vitro reactions, fails to explain the chief properties of poisons. Similarly, the intervention theory which was based on the principles of quantum biology and claimed that the molecule of a poison affects a vital cell centre, fails to give a comprehensive explanation for the action of poisons.

Today it is generally recognized the poisons act on the organism by affecting its enzyme systems.

Apart from those substances which are poisonous because of their capacity to destroy tissues (e.g. corrosive acids and alkalis) or to interfere with membrane permeability (e.g. carbon tetrachloride) most toxic compounds act by preventing or inhibiting the normal enzymatic processes responsible for the maintenance of living cells, but only in a few cases has the process been worked out in any detail.  The majority of toxic compounds are chemically stable and produce their characteristic effects by interference with biochemical or physiological homeos­tatic mechanisms. Cellular damage is the basis for most toxicologic injury, how­ever, many adverse events are the consequence of disturbance of normal physiology and do not result in cell death. Mechanisms of action of toxicants can be broadly classified into two major groups, i.e. toxicants having specific actions and non-specific actions.

I. Specific Action of Toxicants

1. Receptor mediated events: The actions at the specific receptors for neuro-transmitters, hormones, and drugs either as agonists or as antagonists are responsible for numerous toxic responses. This is most important for neurotoxins acting within and outside the central nervous system, e.g. strychnine, morphine and atropine.

2. Enzyme mediated events: Some toxicants interact directly with specific enzymes which catalyze some important physiologic processes to produce their toxic effects. The severity and duration of poisoning can be influenced by the strength of toxicant-enzyme interaction.

 e.g.  Organophosphorus and carbamate insecticides produce their toxicity through inhibition of cholinesterses.

HCN by cytochrome oxides.

Lead via inhibition of membrane bound Na+-K+, - ATPase, δ-aminolevulinic acid synthetase and ferrochelate, etc.

II. Non-specific Action of Toxicants

1. Physical toxicants: Certain toxicants act by their physical deposition in body tissues, and organs like lungs, e.g. industrial and heavy metals dust, silicon, and asbestos.

2. Direct chemical injury: Direct chemical injury to tissues either causes protoplasmic precipitation or alters the membrane dependent homeostatic con­trol of cell functions. Damage is usually immediate, localized and non-specific. Damage occurs when cell membranes contact strong corrosives, caustics or compounds that coagulate proteins or damage lipids, e.g. acids, bases, phenols, aldehydes, alcohols, petroleum distillates and some salts of heavy metals.

3. Necrosis of epithelial cells: Systemic toxins can cause epithelial necrosis mainly by producing ischaemia (reduced blood flow) resulting in damage to metabolically active cells. Damage mainly occurs due to cellular anoxia which further leads to an energy deficit, e.g. carbon monoxide, cyanide, and nitrite.

4. Interference with body metabolism or synthesis: This leads to loss of products used for energy, structural components and growth. This may take place in following ways:

a. Uncoupling of oxidative phosphorylation: The release of energy in the electron transport chain becomes uncoupled from the formation of energy. This results in no phosphorylation of adenosine diphosphate (ADP) to adenosine triphosphate (ATP). The energy is dissipated as heat rather than stored in high energy phosphate bonds. Thus, body temperature rises, e.g. dinitrophenol and chlorophenol fungicides, and arsenates.

b. Inhibition of oxidative phosphorylation: This results in limited oxygen uptake with lower ATP formation. The effects of fatigue and weakness are similar to that of oxidative uncouplers but there is no fever.

C. Inhibition of nucleic acid and protein synthesis: This can occur by toxicants that injure DNA or that bind to ribosomes during transcrip­tion or translocation, e.g. aflatoxins, organomercurials, and trichot­hcccncs,

d. Interference with fat metabolism: This occurs when toxins affect the rough endoplasmic reticulum resulting in reduced synthesis of lipid acceptor proteins or reduced incorporation of phospholipids and triglycerides into transport lipoproteins. This leads to fat accumulation in the cell, e.g. carbon tetrachloride, ethionine, yellow phosphorus, and puromycin.

5. Injury to blood, vascular and respiratory system:

Hypoplasia or aplasia of cellular components of blood may result from direct toxic effects on bone marrow precursor cells. e.g. Chloramphenicol, radiations, etc.

Coagulopathy from toxic interference with Vit. K results in spontaneous haemorrhages. e.g. rodenticides such as warfarin and brodifacoum prevent the reactivation of Vit. K needed for the synthesis of prothrombin and factors VII, IX and X.

Causing lysis of erythrocytes: e.g. Haemotoxic venoms.

Inactivating haemoglobin: e.g. Nitrites, CO, Chlorate, etc.

Interfering with oxygen exchange in pulmonary alveoli: ANTU, paraquat, etc.

Interfering with cellular utilization of oxygen: Cyanide, H₂S, Fluoroacetate, etc.

6. Deposition in tissues/organs: Certain toxicants have special affinity for some organ and tissue, thus producing their toxicity.

For example, fluoride deposition in bones and teeth produces exostosis of bones and mottling of teeth; and sulphonamide and oxalate crystals deposition in kidneys produces nephrotoxicity.

Causing abnormalities in long bones – Fluorine, Lead, Selenium, Copper, etc.

Causing painful lesions in feet: Ergot and other mold toxins, fluorine, etc.

Bone cartilages and joints: Fluoroquinolones.

Liver: CCl4, Chloroform, paracetamol, lantadenes, pyrrolizidine alkaloids, etc.

Kidney: lead, mercurial salts, aminoglycoside, etc.

CNS: lead, mercury, barbiturates, strychnine, etc.

7. Action on ion permeability/channels: Excitable membranes are critical to the function of nerves and muscles to generate and propagate action poten­tial. Interaction with ion-channels and membrane ion-pumps can be influenced by a variety of toxic compounds.

e.g. neurotoxicity of chlorinated hydrocarbons (DDT, aldrin) and pyrethroids (fluvalinate, deltamethrin), tetrodotoxin, saxitoxin, etc. is the result of interference with  sodium channels.

8. Altered calcium homeostasis: Calcium ions have critical roles in cellular function whose concentration is tightly controlled by a variety of compartmen­tation processes and transport mechanisms. Various toxicants can disrupt these with marked deleterious effects on the cell, i.e. changes in the cytoskeleton, leakage from plasma membrane, impaired mitochondrial function and activation of calcium dependent degradative enzymes (proteases, phospholipases, en­donucleases), e.g. free radicals, quinones and peroxides.

9. Formation of secondary toxic metabolites: Certain compounds after their biotransformation, results in metabolites which are more toxic. For example, urea toxicity occurs due to release of ammonia, and carcinogenicity is produced by active metabolites of aflatoxins.

10. Action similar to normal metabolite or nutrient: Some toxicants resemble endogenous substances in their structure and can mimic their activity but in higher magnitude which produces toxic effects. For example, oestrogenic mycotoxins (zearalenone), plants, and feed additives may alter reproductive cycle due to their structural resemblance with endogenous oestrogens.

11. Immuno-deficiency: Toxicants can affect both humoral and cell­ mediated immunities. Reduced antibody synthesis, interference with comple­ment, altered neutrophil function and reduced lymphoblastogenesis are all toxic effects mediated by various agents, e.g. heavy metals (lead, nickel), digoxin, mycotoxins, drugs, and insecticides.

12. Developmental defects: These defects occur primarily in utero as a result of toxicants affecting susceptible cells during organogenesis. Most teratogenic effects altering the morphology of the foetus occur in the first trimester of pregnancy e.g. benzimidazole anthelmintics. Toxicant exposure in the third trimester results in reduced growth of a foetus, e.g. thalidomide, tetracyclines, heavy metals, and quinine.

13. Carcinogenesis: Promotion of carcinogenesis is caused by chemicals that produce tissue irritation or damage to macromolecules resulting in expres­sion of the cancer process. This is mainly due to DNA damage, e.g. insecticides (DDT), hormones (oestrogen), and saccharrin.

14. Deficiency of nutrients: Certain toxicants produce deficiency of essen­tial nutrients in the body. However, such effects produced by these chemicals are secondary. For example, molybdenum produces toxicity due to deficiency of copper; oxalate chelates Ca⁺⁺ in the rumen and blood to produce hypocal­caemia (oxalate poisoning).

15. Non-specific action on enzymes: Certain toxicants inhibit certain non­specific enzymes to produce their toxic effects. For example, rubratoxins inhibit cytochrome P450 mixed function oxidases besides certain ATP-ases.