Ouabain is a cardiac glycoside which results in elevated levels of calcium and sodium concentrations, by inhibiting the ATP dependent sodium-pottasium membrane pump (Sergeev and Valeeva, 1998). Its restricts the necessary conformational changes, hence affecting the intracellular ion composition. Increased intracellular calcium levels causes contractile protein activation and increase contractile strength in cardiac muscle cells. Adhesion to the sodium-pottasium pump is facilitated by the hydroxyl groups surrounding the molecule. Polar residues such as aspartic acid, glutamine, threonine, along with amide alanine bond surround the carbonyl and hydroxyl groups of the ligand forming hydrogen binds to confine the drug in place. Inhibition of the sodium potassium pump causes increased sodium, hence activating the sodium calcium pump which again results in an influx of calcium in the cytoplasm. This drug was able to treat patients suffering of arterial fibrillation and acute/chronic heart failure by increasing phase 4 depolarisation slope, by acting on the electrical conduction of the heart, thereby minimising the duration of action potential leading to a reduced maximal diastolic potential(Ogawa et al., 2009).
‘-amanitin is a heat stable bicyclic octapeptide, which inhibits the action of enzyme RNA polymerase II (RNAPII). This mushroom toxin specifically and selectively restricts transcription in RNAPII, and binds to the RPB1(largest subunit of RNAPII) with high affinity, preventing translocation. Funnel shaped active site located beneath a bridge helix, localised in a fissure between two largest polymerase II subunits (Rpb1 and Rpb2). Transcription inhibition leads to redundant messenger RNA production, thereby ceasing protein synthesis resulting in cell death with 24 hour span. Bondage between polymerase II and ??-amanitin allows RNA synthesis and the nucleotide entry to the active site, although the translocation of RNA and DNA from the active site is inhibited (Bushnell, Cramer and Kornberg, 2002). Greatest degree of damage was caused to intestinal mucosa cells with the highest multiplication rates, followed by hepatocytes and cells of kidney tubules. This can lead to renal failure, coagulation disorders, hepatic coma and liver necrosis associated with hepatic failure, due to the restricted protein synthesis in the ribosomes (Nguyen, 1996).
8. Pyrrolizidine Alkaloids (PAs)
Pyrrolizidine alkaloids toxins are released from plants as a defence mechanism to protect from insect herbivores, with its hydrolysis products being; necic acid and necine base. Its genotoxicity is resulted by the metabolic activation which occur through one of the following main three metabolic pathways; formation of necine bases by the hydrolysis of the functional ester group, formation of necine N-oxides from the oxidation of corresponding necine bases and, formation of 8- or 3-hydroxynecine derivatives by hydroxylation of necine base at C-8 or C-3 position followed by dehydration to form its respective dehydropyrrolizidine derivatives. CPY2B6 andCYP3A isozymes located in P-450 cytochromes in responsible for the oxidation of PAs to dehydropyrrolizidines, which are reactive alkylating agents (Robertson and Stevens, 2014). PAs are absorbed from the digestive tract and travels to the liver where it damages the liver cell, causing hepatic sinusoidal obstruction syndrome and liver cell necrosis. Genotoxicity also involves, DNA cross linking, DNA binding, DNA-protein cross linking, carcinogenicity and mutagenicity as the metabolites alkylate DNA (Fu et al., 2002).
Agatoxins present in the venom ejaculated by Agelenopsis aperta species target three ion channel classes namely; voltage-activated sodium channels, voltage-activated calcium channels and glutamate-activated receptor channels. Different classes of channel specific toxins exhibit varying mode of actions (Uchitel, 1997). ‘-agatoxins occlude postsynaptic glutamate open channel receptors at the neuromuscular junction preventing the development of excitatory jump potential. This results in reversible rapid paralysis in mammals and insects, with severities including hypotension and elevated inter-cranial pressure due to cerebral oedema. ??-agatoxin acts as an antagonist blocks the presynaptic calcium channels preventing transmitter release in the synaptic cleft. Symptoms include progressive paralysis, eventually causing death. ??-agatoxins elevates repetitive action potentials and spontaneous transmitter release in motor neurone, transposing to increased negative potentials by voltage-activated sodium ion channel modifications. This constituent of venom results in long-lasting and rapid paralysis, causing both inhibitory and exhibitory effects at the neuromuscular junction which can lead to death of insects(Adams, 2004).
Dimercaprol is a dithiol chelating agent, used in the treatment of heavy metal poisoning such as mercury, gold, arsenic and lead, due to its high affinity for sulfur seeking metals. It was primarily used as an antitoxin to heavy metal-chelating warfare agent Lewisite, which caused spontaneous blistering and pain upon contact, with exposure to eyes causing potential blindness. It was used in treatment of Wilson’s disease which is caused as a result of surplus of calcium accumulated in the liver and the brain. Formation of heterocyclic ring complexes with the sulfhydryl groups of dimercaprol reverse or minimises heavy metal cations from binding to body ligands, by accepting pairs of free electrons from sulphur groups of the chelating agent . Due to its minimised association with important biological molecules, considerably low toxicity to them, rapid penetration to the congested tissue containing heavy metal ions, reduced metabolism and the speedy excretion of the chelated metal enables treatment of heavy metal poisoning(Vilensky and Redman, 2003).
...(download the rest of the essay above)