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Natural Toxins and Their Therapeutic Potential

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Natural Toxins and Their Therapeutic Potential Indian Journal of Experimental Biology Vol. 48, March 2010, pp. 228-237 Review Article Natural toxins and their therapeutic potential V K Kapoor G H G Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana 141 104, India Plants have been extensively investigated for exploring their therapeutic potentials, but there are comparatively scanty reports on drugs derived from animal kingdom, except for hormones. During last decade, the toxins that are used for defense by the animals, have been isolated and found useful tools for physiological and pharmacological studies, besides giving valuable leads to drug development. Toxins with interesting results have been isolated from the venoms of snakes, scorpions, spiders, snails, lizards, frogs and fish. The present review describe about some toxins as drugs and their biological activities. Some fungal, bacterial and marine toxins have also been covered in this article. Keywords: Animal toxin, Fungal toxin, Natural toxin, Therapeutic use, Venom Natural toxins, whether derived from plants, fungi, stereoisomers, is the most active coronary marine organism, snails or animals have played a vasoconstrictor acting through interaction with calcium significant role directly or indirectly in drug channels. Palytoxin is the most poisonous non- development. The first of the angiotensin converting proteinaceous substance has been isolated from enzyme (ACE) inhibitor captopril owes its discovery zoanthid coral Palythoa toxica . It is used as a to venom of the poisonous Brazilian viper, Bothrops physiological tool to evaluate anti-anginal juraraca. Bakhle 1 has reported that peptides from the chemotherapeutic agent. Toxins like betrachotoxins , Brazilian viper venom inhibit the activity of ACE tetrodotoxin , saxitoxin, have not only given new leads, present in cell-free extracts of dog lung. Captopril but have given impetus to neurophysiology and emerges 2,3 as a drug used in the management of pharmacology by acting as pharmacological tools. hypertension, and in heart failure after myocardial Molecular aspects of electrical excitability in nerve, infarction. Exendin-4, a peptide isolated from the skeletal muscle and cardiac cell can be elucidated with venom of gila monster, Heloderma suspectum , a the help of natural toxins. The present communication species of poisonous lizard from North America presents an account of recent advances made in natural exhibits a significant amino acid homology with toxins and their role in drug development. 1 glucagon-like peptide (GLP-1) secreted from intestinal L-cells. Extendins are carboxy-amidated Plant toxins peptides containing 39 amino acid residues. Extendin- Fungal toxins Among the toxins obtained from 4 stimulated insulin secretion in vitro and is a potent different fungi aflatoxins are the most documented of 4 agonist of the GLP receptor . Studies in diabetic mice all mycotoxins. Aflatoxins are closely related group of have shown long-lasting reduction of blood glucose secondary metabolites produced by Aspergillus flavas concentration following once daily injection. and A. parasiticus . Improper storage of crop products Synthetic extendin-4 (exenatide) was licensed in 2005 often results in their contamination by these for the treatment of type-2 diabetes in combination toxicogenic moulds. Thus, aflotoxins have been with metformin and/or sulphonylureas when either reported to naturally occur in plants, corns, cotton seed, 5 drug, alone or in combination, is inadequate . groundnuts and peppers, etc. There are four naturally Palytoxin 6,7 , one of the most complicated natural occurring aflotoxins (B 1, B 2, G 1 and G 2). Chemically, product with sixty four chiral centres and seven aflotoxins are fluorescent compounds characterized by double bonds allowing a large number of a dihydrofuran or tetrahydrofuran moieties fused to a substituted coumarin heterocycle. The aflotoxins are ______________________ listed as known human carcinogens 8, aflatoxin B (1) Telephone: 0172-2632496; 1 Fax: 01624-275469 being one of the most potent environmental mutagens Email: vikkuips @yahoo.com and carcinogens known. KAPOOR: NATURAL TOXINS & THEIR THERAPEUTIC POTENTIAL 229 H C CH3 O 3 O O O O O O H3C O O O CH3 O O Cl H3C (1) (2) Fig. 1 Structure formulae of compounds ( 1) and ( 2) Mycotoxins 9 produced by Fusarium species, deadliest nerve poisons known throughout history. It represented by trichothecenes, zearalenones and is estimated that an oral dose of 70 µg or inhalation of fumonisins also affect animal and human health and a hundredth of that amount is enough to lethally possess divergent biological activities. Zearalenone a poison an average adult and most dreaded as β-resorcylic acid lactone, is reported to have biological weapon 14 . The toxin blocks the release of hyperestrogenic activity in mice 10 . Ochratoxin A, acetylcholine from presynaptic nerve terminals roquefortine and citrinin are some of the toxicants of causing a generalized paralysis of the muscle resulting genus Penicillium associated with human and animal in death. Its name is derived from “botulus”, Greek disease 11 . Griseofulvin (2) a toxicant from P. for sausage, the food linked to many outbreaks of griseofulvum is used as antifungal drug. Panigrahi 12 botulism 15 . Botulin toxin has been used as an has reviewed the mycotoxins of the genus Alternana investigational agent for the study of synaptic and discussed their toxic activities. neurotransmission. Besides, it has proven to be an A mention may be made of amanitin and extremely useful therapeutic agent for clinicians to phalloidin, the cyclopeptide toxins from the poisonous treat various gastrointestinal smooth muscle disorders. mushroom Amanita phalloides . Amanitin is mixture Its use in the treatment of achalasia is well of α-, β-, γ-amanitin and amanin. α-Amanitin, which documented 15 . Botulin A and B have been approved is the major constituent, is 10-20 times more toxic for clinical use. Recently, use of botulinum toxin in than phalloidin. Development of cyclosporin A the treatment of chronic anal fissures has been (ciclosporin A) as an immunosuppressive drug has reviewed 16 . Relief of post-radiotherapy masticatory been traced back to the stimulus derived from the first spasms 17 , and inducement of certicospinal excitability highly-active cyclopeptides from Amantia changes in a population of patients with limb mushrooms. spasticity 18. Algal toxins Anatoxins represent first neurotoxins Marine toxins A mention has already been made present in fresh-water blue-green alga Anabaena flos- of palytoxin, a highly poisonous toxin from zoanthid aquae . Anatoxin-a is the strongest agonist known for coral Palythoa toxica used as a physiological tool. the nicotinic acetylcholine receptor 13 . Despite its Other marine toxins of medicinal interest are apparent structural dissimilarity to the natural didemnins which are depsipeptides extracted in 1978 transmitter acetylcholine, the physiological effects of from a Caribbean tunicate (sea squirt) of the genus the toxin are identical with those of acetylcholine. Trididemnum 19 . Although more than nine didemnins Anatoxin-a is about 30 times more potent than (A-E, G, X and Y) have been isolated from the extract carbachol (carbamylcholine). of Trididemnum solidum , it is didemnin B (3) that Bacterial toxins The anaerobic bacterium possesses the most important biological activities 20 . Clostridium botulinum produces a family of potent- Didemnin B is a strong antiviral agent active against neurotoxins collectively called as botulin toxins. both DNA and RNA viruses like Herpes simplex virus Seven serologically distinct types are known type 1, and a strong immunosuppressant that shows designated as botulin A, B, C, D, E, F and G. some potential in skin graft 21 . It shows strong activity Botulinum toxin has long been known as one of the against murine leukemia cells. It has undergone phase 230 INDIAN J EXP BIOL, MARCH 2010 II human clinical trials against adrenocarcinoma of presynaptic phospholipase A 2 neurotoxin, consists of kidney 22 , advanced epithelial ovarian cancer 22 and two dissimilar polypeptide chains (chains A and B) metastatic breast cancer 21 . Unfortunately, it has shown cross-linked by an interchain disulphide bond. The high toxicity and anaphylactic reactions in patients larger chain contains 120 amino acid residues, the resulting in terminating the trials 24 . smaller chain contains 60 residues. It has been suggested that both A and B chains are indispensable Animal toxins parts of β-bungarotoxin for inducing the facilitation of spontaneous synaptic currents frequency with Venomous animals possess a wide range of toxins 27 for predation and defense. It is difficult to Xenopus nerve-muscle cultures . Recently, it has comprehend the exact number of venomous species or been indicated that both A and B chains possess the the number of toxins they produce. A number of capability to induce vesicle leakage, and reduction of interchain disulphide bond markedly releases this venomous animals and their toxins have been 28 investigated to explore their biological activities and ability from intact β-bungarotoxin molecule . therapeutic potential. Among the animal, toxins of The venom of Vipera russelli produces alterations snake, scorpion, spider, snail, lizard, frog, fish and in general behavioral pattern, reduction in insect have been described as follows. spontaneous motility, hypothermia, potentiation of 29 Snake toxins Snake venom is a mixture of both hypnosis, analgesia, and muscle relaxation . proteinaceous
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