Action of Naturally Occurring Toxins and Medicines
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The purpose of this review is to study ten different toxins and what changes they cause in the human body which will then lead to observable signs and symptoms. Naturally occurring toxins are obtained from organisms such as animals, plants (Dolan et al. 2010) and others while medicines are drugs used to treat or prevent a disease. A medicine can either be natural or synthesized.
Cobratoxin or most commonly known as α-cobratoxin is a constituent of the venom of cobras of the Naja genus. This toxin is a nicotinic acetylcholine receptor antagonist (nAChR) and its binding to neuron and muscle type nAChRs is reversible yet very slow. This interaction to the receptor will prevent acetylcholine from binding hence this will inhibit the flowing of ion through the postsynaptic membrane which in turn result in paralysis (St Pierre et al. 2007). α-cobratoxin prevents the nAChRs from twisting (opening mechanism) to allow ion flux. A cobra bite would swell and become painful and also lead to the blackening of the bite. Moreover, necrosis is observed which will keep hurting the person even years after the biting. The first symptom observed is palpebral ptosis since the ocular muscles are more vulnerable (Del Brutto and Del Brutto, 2012). Then within a few hours, facial, neck and respiratory muscle are paralyzed and the victim dies due to lack of oxygen as a result of breathing difficulty.
Charybdotoxin is a neurotoxin which is a substance of the venom of the Leiurus quinquestriatus hebraeus scorpion. This toxin targets Ca2+ activated potassium Channel. Charybdotoxin prevent the movement of K+ movement by obstructing the pore of the calcium activated potassium channel and this leads to the prolonged duration of an action potential. Since the efflux of potassium is reduced, the membrane potential increases. Therefore, there is an increase probability in the initiation of an action potential which will result in the hyperexcitability of the nervous system (Moretti et al. 2012). The hyperexcitability of the nervous system will in turn cause inflammatory response and hence develop symptoms such as pain due to sting, cases of anaphylaxis, respiratory problems and in worst case death.
- Pertussis toxin
Pertussis toxin is an exotoxin manufactured by the bacteria Bordetella pertussis. This bacterial is responsible for the whooping cough disease. It consists of 5 subunits namely S1-S5 organized in an A-B structure. It binds to cell receptors of the upper respiratory tract. Pertussis toxin is mono ADP-ribosyltransferase which alters the α-subunit of Gi proteins covalently. Pertussis toxin moves into the host cells by endocytosis. It causes the ADP-ribosylation of G proteins. The S1 subunit causes hydrolysis of cellular NAD and the resulting ADP-ribose is then transported to a specific cysteine residue in the C-terminal of the G proteins’ α-subunit. Therefore the process of ADP-ribosylation will cause the inhibition of Gi protein-coupled signalling pathways (Carbonetti, 2010) and this affects intracellular communication. The Gi subunits stays in their inactive state and as such are incapable of inhibiting adenylyl cyclase activity. Therefore, the cAMP level in the cell increases and this disturbs the biological signaling. It has been found that when Pertussis toxin increases cAMP level, there has been an associated hyperinsulinemia and hypoglycemia (Blumberg et al. 1993).
Colchicine is a naturally occurring toxin as well as a secondary metabolite of the tricyclic alkaloid molecule which can be obtained from the plant of genus Colchicum. This toxin is most commonly used to treat gout, cases of pericarditis and also Familial Mediterranean Fever. Colchicine binds to free tubulin dimers and when it is merged with emerging microtubules, it will additional disturbs the microtubular polymerization. Imapired microtubule polymerization results in cells not being able to assemble proteins properly and also inhibition of phagocytosis, migration and division (Finkelstein et al. 2010). Moreover, the cells experience altered morphology, a decrease in motility, stoppage of mitosis, decrease in the rate of endo/exocytosis and disturbed contraction and conduction of cardiac myocytes. All these will lead to organ malfunctioning and organ failure. Colchicine inhibits intracellular signaling molecules during phagocytosis. They also modify neutrophil so as to prevent neutrophil extravasation. Finally, the also increase the leukocyte cAMP level and this results in the impaired neutrophil function (Paschke et al. 2013) Common side effects are vomiting, nausea and diarrhea.
Tetrodotoxin is a guanidinium compound which is a natural neurotoxin. It is manufactured by bacteria in puffer fish. It targets the voltage gated Na+ channels proteins in nerve cell membranes. The effect of tetrodotoxin is shutting down electrical signaling in nerves by obstructing the sodium channel. It competes with the Na ion for the sodium channel. The binding is by the guanidinium group (+ve) to the carboxylate group (-ve) on the sodium channel (Dengâ€Fwu H. and Tamao, 2007). The guanidinium fits right into the channel, however, the other part of the molecule is too big for the channel. Therefore, it acts like a “cork”. Hence the channel is blocked and sodium cannot move inside. This in turn stops the conduction of nerve impulses along the nerve fibres as well as axons (Chen and Chung, 2014). The first symptom is usually observed within 15 minutes. The early symptoms are lip and tongue paresthesias followed by respiratory muscle paralysis and finally cardiac dysfunction and ultimately death between four to six hours.
Ouabain is a cardiotonic stereoid and is also known as g-strophanthin. Ouabain targets the sodium/potassium pump. It binds to the α subunit of the Na,K-ATPase and causes the inhibition of enzymatic function. Oubain is secreated from the adrenal glands. It is used as a poison in arrows. When the arrow cuts the skin, ouabain enters the bloodstream. Then it binds to the α subunit of the Na,K-ATPase and increase the amount of Na+ that enters the cell (Wang et al. 2001). As a result, this causes the level of calcium to increase in the cell and hence make the heart beat more rapidly. Large doses of the ouabain can be fatal as it can cause cardiac arrest. However, small doses are used to increase heart function and can be used to treat heart diseases. In myocardial cells, ouabain causes a series of phosphorylating events which activates mitogen-activated protein kinase--extracellular signal regulated kinases which in turn leads to gene expression causing cell proliferation (Xie and Cai, 2003). Over exposure to ouabain can cause heart arrhythmia, respiratory problem, cardiac arrest and even coma.
α-amanitin is a cyclic peptide which is the most lethal of all amatoxins. It is present in mushrooms of Amanita genus. It targets eukaryotic cells where it binds and inhibit nuclear RNA polymerase. Lesions are observed specially in hepatocytes as well as kidney tubular cells. The hepatocytes take up the toxin rapidly and excrete the latter into bile. α-amanitin inhibits RNA polymerase both at the initiation and elongation stages during transcription. α-amanitin binds to the cleft in RNA polymerase which is itself connected to a helix bridge. Hence the movement of the bridge is impaired and this results in a significant decrease in the rate of translocation (Gong et al. 2004). α-amanitin poisoning has a rather long incubation time of six to twelve hours and the symptoms are usually vomiting, diarrhea, abdominal pain dehydration and hypoglycemia. Days later, hepatocellular damage will be observed and clotting disorder will occur. In many circumstances, victims suffer acute liver failure, renal failure, hemorrhage and sometimes coma (Thiel et al. 2011).
- Pyrrolizidine Alkaloids
Pyrrolizidine Alkaloid is a natural alkaloid produced by plants to be used as a defense mechanism. This substance causes veno-occlusion (blockage of veins present in the liver) due to the binding of the metabolite to the nuclei of hepatocytes cell. Pyrrolizidine Alkaloid are chemically unreactive and require bio activation to produce toxic metabolite for toxic action to be observed. The liver is the organ which metabolize the alkaloid hence liver problems are usual. Oxidation will produce toxic metabolites (pyrroles) and the latter will bind to DNA, protein and amino acids very quickly. As a result of this binding, cellular functions are altered and cells are damaged. The crosslinking to DNA can instigate cancer formation (Castells et al. 2014). Prolonged exposure to Pyrrolizidine Alkaloid mostly damages the liver, lungs and blood vessels. Less damage occurs in kidney, pancreas and gastrointestinal tract. Venous occlusion occurs mainly in the liver as well as the lungs. Other cases such as megalocystosis, liver cirrhosis as well as genetic effects are seen.
Agatoxins are a polyamine and peptide toxins which differ from each other chemically. They are obtained from the venom of spiders such as Agelenopsis aperta. The agatoxins can be further divided into 3 subclasses, namely, alpha-agatoxin, omega-agatoxin and Mu-agatoxin. Alpha-agatoxin targets glutamate activated receptor channels which are present in the neuronal postsynaptic terminals. When blocking occurs, they prevent the development of excitory junction potential. This toxin creates a rapid yet reversible paralysis. Progressive hypotension can lead to death. (Adams, 2004) Omega-agatoxin targets Ca2+ channel present in the neuromuscular junction (the presynaptic terminals). As a result, there is reduced calcium influx which in turn cause a decrease in the releasing of neurotransmitters in the synaptic cleft. Finally mu-Agatoxin targets presynaptic voltage activated Na+ channel which are found in neuromuscular joints. They modify the sodium channel which then causes an increase in the latter sensitivity. As a result, the frequency of release of neurotransmitters, action potential in motor neuron and postsynaptic excitatory currents are increased. The bite of the spider may cause metabolic acidosis, facial twitching, vomiting and coma due to hypertension (Adams, 2004).
Dimercaprol is a synthetic compound produced for the treatment of lewisite (arsenic based chemical weapon) and poisoning by heavy metals. Dimercaprol itself is a toxic drug but small therapeutic dosage can be used. Dimercaprol contains sulphydryl group and these groups contest with endogenous sulphydryl groups on proteins (e.g. enzymes) to bind to the heavy metals (Soares et al. 2003). Dimercaprol chelation avoid/reverse the inhibition of the sulphydryl group containing enzymes by the heavymetals. Therefore a dimercaprol-heavymetal complex is produced and the latter is freely excreted by the kidney. The intramuscular injection of dimercaprol is very painful and is accompanied with many side effects namely; blood, lymphatic, nervous system, eye, respiratory disorders, tachycardia and hypersalivation (Sears, 2013). When injected, dimercaprol is widely distributed throughout the whole body. However, the concentration is highest in the kidney as well as the liver. The complex (dimercaprol-heavymetal) is excreted via urine. The symptoms appear immediately after injection and recede within two hours.
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