Toxicants, natural toxins

At this time, a solid phase automatic peptide synthesizer was acquired, so we attempted total synthesis of Sh I. A solid phase synthesis of Ax I (antho-pleurin A) had previously been reported in an abstract (36). The synthetic Ax I possessed only 11% of the toxicity of the natural toxin. 

First, we investigated whether Sh I could be reduced under denaturing conditions, exposed to the hydrogen fluoride cleavage procedure we intended to use, then reoxidized and refolded successfully. The toxicity of the resulting polypeptide (50% yield) was the same as that of the untreated natural toxin. 

There are many different kinds of toxicants. Chemicals that are used for industrial and household purposes can be poison when misused or when there is an accident. Agricultural pesticides in the field can also cause poisoning. Chemicals might come in the form of conventional drugs which we use in a legitimate way, or in the form of designer drugs used illicitly for recreational substance abuse. Natural toxins found in the environment, such as mushrooms, plant toxins, snake/insect toxins and marine toxins, can also inadvertently harm a patient. 

Evolution is tireless in the development of natural toxins. A vast number of variations are possible with even a small number of amino acids in peptides, and peptides make up only one of a broad array of toxic compounds. For example, the predatory marine snail genus Conus is estimated to include at least 500 different species. Each species kills or paralyzes its prey with a venom that contains 50-200 different peptides or proteins. Furthermore, there is little duplication of peptides among Conus species. Other animals with useful toxins include snakes, frogs, spiders, bees, wasps, and scorpions. Plant species with toxic (or therapeutic) substances are too numerous to mention here they are referred to in many chapters of this book. 

The first total synthesis of a phallotoxin was that of norphalloin, the norvaline analogue of phalloidin.16 This synthesis, outlined in Scheme 2, initially involves the synthesis of two building blocks followed by their covalent binding via a tryptathionine moiety. Subsequent deprotection and coupling steps using classical methods of peptide synthesis results in the formation of norphalloin, which has proved to be even more toxic than the natural toxins. Since the synthesis of norphalloin, a number of synthetic analogues have been synthesized in order to obtain information on structure-activity relationships.[7 8]... 

The Dutch-Danish 1991 philosophy paper highlighted that the Codex definition of a contaminant does not include inherent natural toxins (e.g. the glucosinolates and phycotoxins), since these substances are present in food as a result of the metabolic processes in the organism. It was then decided to have the GSCTF also to include such toxins, as they may in many ways be similar to contaminants. Many toxins are at least as toxic to humans as most contaminants, and they may also cause problems in international trade.10 It was also recommended and agreed by the CCFAC that the GSCTF should be based upon a horizontal approach, i.e. covering the important contaminants in all relevant foods, and that the MLs should be set as low as reasonably achievable - the ALARA principle. 

In contrast, mono- and oligophagous species often select their host plants with respect to the composition of the nutrients and secondary metabolites present. For these specialists the originally noxious defense compounds are often attractive feeding and oviposition stimulants. These insects either tolerate the natural products or, more often, actively sequester and exploit them for their own defense against predators or for other purposes 1,4,10-12,14-17,28,31,33,494-496). These observations seem to contradict the first statement, that secondary metabolites are primarily defense compounds, and a number of renowned authors have fallen into this logical pit, such as Mothes 35) and Robinson 505). However, these specialized insects are exceptions to the general rule. For these specialists, the defense chemistry of the host plant is usually not toxic, but they are susceptible to the toxicity of natural toxins from non-host plants 32). As compared to the enormous number of potential herbivores, the number of adapted monophagous species is usually very small for a particular plant species. 

Truelove, J., Mueller, R., Pulido, O., Martin, L., Femie, S., and Iverson, F. 1997. 30-day oral toxicity study of domoic acid in cynomolgus monkeys lack of overt toxicity at doses approaching the acute toxic dose. Natural Toxins 5, 111-114. 

Yoshida, T, Makita, Y, Nagata, S., Tsutumi, T, Yoshida, E, Sekijima, M., Tamura, S., and Ueno, Y. 1997. Acute oral toxicity of microcystis-LR, a cyanobacteria hepatotoxin, in mice. Natural Toxins 5 91—95. 

Natural toxins in food can be divided into five main categories my cotoxins, bacterial toxins, phycotoxins, plant toxins and zootoxins. The first three are toxic compounds produced by living organisms, and are formed directly in food or transferred through the food chain, whereas, the latter two are inherent components (of plants or animals) that are harmful to humans and animals [1]. 

In the West Indies especially, pyrrolizidine alkaloid toxicity is a continuing problem, as plants containing pyrrolizidine alkaloids such as Heliotropium, Senecio, and Crotolaria species are used in traditional medicine to make herbal teas. Chronic exposure to low doses of these alkaloids causes liver cirrhosis, and it is estimated that these alkaloids account for one-third of the cirrhosis cases detected at autopsy in Jamaica (see Chapter 6 for more details of these natural toxins). 

Onchidal and fasciculins are natural toxins, which produce their toxicity in mammalian systems by virtue of primarily acetylcholinesterase (AChE) inhibition. AChE hydrolyzes and inactivates acetylcholine, thereby regidating the concentration of the transmitter at the synapse. Termination of activation is normally dependent on dissociation of acetylcholine from the receptor and its subsequent diffusion and hydrolysis, except in diseases where acetylcholine levels are limiting or under AChE inhibition, conditions that increase the duration of receptor activation (Silver, 1963). 

Onchidal and fasciculins are interesting natural compounds and it is difficult to predict their toxicity. In the case of onchidal, in silico computational predictive modeling for toxic endpoints of interest may prove useful for risk assessment decision support. Likewise, it is a challenge to predict the mditary potential and human impact of these natural toxins since their affinity for enzyme inhibition depends upon the amount and duration of the human exposure. 

SAFETY PROFILE Poison by ingestion, intravenous, and subcutaneous routes. An experimental teratogen. Experimental reproductive effects. A natural toxin found in some plants. When heated to decomposition it emits toxic fumes of NOx. 

From an epidemiological point of view, among the causes of AKI of a medical nature, drug-induced and toxic AKI are very important [77]. Nephrotoxic substances include a wide variety of compounds such as heavy metal ions, organic solvents, antibodies and natural toxins. Nephrotoxins induce AKI in humans by direct cellular toxicity, vasoconstriction, and crystal-mediated tubular obstruction. Acute interstitial inflammation is an important factor in pathogenesis of acute interstitial nephritis. In general, a decrement of... 

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