Poisonous Plants and Phytochemicals in Drug Discovery. Группа авторов
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Brief Mechanisms of Action
2.1 Introduction
Phytotoxins are basically toxic secondary metabolites that are found in plants. They largely have low molecular weight and are capable of deranging vital plant physiology and plant cell activities and/or causing the death of a plant at less than 10 mM concentrations [1]. There are hundreds of such substances in a single plant in addition to non‐toxic chemicals, which demonstrates the complexity of phytochemical systems. Phytotoxins can be synthesized by the plants themselves [2], by endophytes (bacteria, fungi, etc.) in the plants [3], and also by phytophagous insects [1].
Phytotoxins can be categorized into two broad groups: those that have an effect on plant systems and physiology and those that have an effect on animals and humans. Those that affect plant systems and physiology are the ones that enjoy the most scientific limelight; they are most commonly discussed in the field of phytotoxins with a focus on the quality of plant life. There is a relatively narrower discussion on phytotoxins that the plant produces with a focus on elements foreign to and outside the plants themselves, such as predators.
Some of the existing phytotoxins are produced by plants for defense purposes against predators, such as insects, microorganisms, and higher animals. At other times, they are produced in response to infestation by environmental and physical stress, such as extreme drought, humidity, and confinement, e.g. growing under a huge rock.
Although phytotoxins are largely known to show adverse effects on plants such as necroses, chloroses, general suppression of growth, wilting, and spotting of aerial portions [1], they may also produce toxins and other metabolites that are beneficial to drug discovery.
Apart from plant health, phytotoxins have been established as playing a significant role in human health. It is therefore important to categorically detail their important identity characteristics to make it easy to understand how they can be used or controlled when it comes to drug development. In this way, their molecular clustering can more efficiently and conveniently lead to the identification of potential drug scaffolds. This chapter discusses the categorization of phytotoxins within the two broad distinctions stated earlier and relates the same to the risks and benefits that these toxins have for disease management and prevention.
2.1.1 Endophytic Phytotoxins
Endophytes in plants are known to produce compounds that are different than those that the plant produces. One of the earliest studies on phytotoxin categorization was carried out successfully in 1980 by Yoder [4], who used the terms ‘pathogenicity’ and ‘virulence’ of toxins as major descriptors, among others. By pathogenicity, Yoder meant the ability to induce disease(s) or disorder, whereas he used the term virulence to describe the severity of the disorder induced.
Phytotoxins that affect plants are usually further categorized by the target range, from the host's range to a wider radius outside the host plant. These are technically called host selective toxins (HSTs) and non‐host selective toxins (NHSTs) [5], where HSTs affect the plant producing the phytotoxin as it hosts the endophyte while NHSTs have no effects on the host plant but affect other plants around it. The mechanisms of action of most HSTs have elements of pathogenicity, where the endophyte liable for a particular phytotoxin invades host tissues, causing some diseases in the plant. In contrast, it is not clear about the roles of NHSTs in pathogenicity [5–7]. Some authors have suggested that NHSTs are not the only pathogenicity determinants in the plants that they affect and they largely contribute to the virulence of the pathogens that produce the toxins [8]. There is a hypothesis that the compounds that a plant synthesizes resemble those that are formed from metabolic processes of endophytes within its cells [9].
2.1.2 Secondary Metabolites
Plants are known to produce various compounds, some of which are directly beneficial to human and animal health. These compounds are secondary metabolites, synthesized by plants and sometimes associated by endophytic activities. Some secondary metabolites are reported to have allelopathic activities [10] and adversely act on the host plant itself or other surrounding plants.
2.2 Possible Categorization
Depending on convenience and the details available about the phytotoxins under consideration, there are a number of ways of systematically categorizing them into meaningful classes. These could be any from: the biological characteristics, chemical characteristics, occurrence, pharmacological characteristics, taxonomic details, response to growth conditions, or habitat. However, some of these aspects can be carefully combined to better qualify other descriptions. Below are brief discussions on the possible categories that can be used to classify phytotoxins.
2.2.1 Biological Characteristics
Phytotoxins differ in terms of their biological characteristics. These characteristics can emanate from the biology of the responsible endophyte or from the bioactivities that the toxins are reported to exhibit, if already studied. Categorization of phytotoxins based on biological characteristics has been a traditional method of phytotoxin classification [8]. For instance, mycotoxins, secondary metabolites from fungi that adversely affect plants and humans alike, often fatally [11], present a good example of classification based on biological properties. The categorization of mycotoxins and other phytotoxins into two different groups had to be revised. They were made into one group of endophytic phytotoxins after similar biological activities of the toxins, among other characteristics, were noticed [11].
Some wild mushrooms, for example, have phytotoxins such as muscarine and muscimol. When ingested, these toxins cause nausea, confusion, diarrhea, visual challenges, hallucinations, and salivation. Symptoms are key to determining the effects of poisoning and, when their onset is delayed, there is only a very small chance of survival because of delayed intervention.
In the same way, some taxonomic details of the host plant can also be of great significance in categorizing toxins from their respective plants of origin. Chemotaxonomy has already proven to be reliable when markers, such as race, genera, species, and pathotypes, among others, are used to determine the phylogenetic relationships among endophytes responsible for the production of some toxic metabolites with similar traits [1].
2.2.2 Chemical Characteristics
Chemical characteristics are one of the easiest and most convenient ways to classify phytotoxins. This is usually done by examining the chemical structures of the phytotoxins, among other chemical properties. Since chemical structures are easily classified by their biosynthetic pathways, those for phytotoxins can also be done in a similar fashion. For example, phytotoxins from Alternaria and Fusarium pathogens share similar chemical structures [11]. Usually, chemical structures are categorized as polyketides, alkaloids, ribosomal and non‐ribosomal, terpenes producing peptides, and metabolites of mixed biosynthetic origin. Other examples include Stagonospora nodorum and Pyrenophora tritici‐repentis; these are both fungi and are known to produce phytotoxic metabolites that are ribosome‐produced peptides [12].
2.2.2.1 Cyanogenic Glycosides
Cyanogenic glycosides are plant‐based phytotoxins occurring in more 2000 plant species, and some of these species are used as food. Plant foods that contain these phytotoxins include sorghum, cassava, bamboo sticks, almonds, and summer fruits. Their toxicity to humans emanates from the cyanide that they contain; the clinical signs of contamination in humans include elevated breathing rates, dizziness, diarrhea, a reduction in blood pressure, headache, stomachache, nausea, confusion, convulsions, and cyanosis. If the body fails to detoxify these cyanides, it can end up in fatality.