The selective toxicity of a chemical may be on account of any of the following mechanisms: 1. Due to Differences in Translocation Factors 2. Due to Differences in Biotransformation Reactions 3. Due to Presence or Absence of Receptors.
1. Selective Toxicity due to Differences in Translocation of Chemical:
Actually gross morphological, anatomical and cytological differences among various groups of organisms account for differential absorption, distribution and accumulation of chemicals which, in turn, may cause selective toxicity. For instance hexapods, i.e., insects, possess large surface area in comparison to mammals with respect to per unit weight. The large surface area of hexapods causes greater absorption and accumulation of any toxicant applied to kill them.
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It may lead to deleterious effect on hexapods without any or similar effect to other forms of life. As an example, DDT an organochlorine insecticide, has been known to be readily absorbed through the chitinous exoskeleton of insects whereas the same insecticide is poorly absorbed through mammalian skin. Consequently, DDT poses greater deleterious effects on insects only, but not on mammals. Another example is the application of 2, 4-D, a modern synthetic herbicide.
It is generally used to destroy unwanted dicotyledonous weeds in the field of cereals. Actually the leaves of cereal crops are waxy and upright which prevent the penetration of 2, 4-D. On the other hand, it is accumulated in quantity sufficient to kill the dicotyledonous weeds from the fields which are rough in texture and wax-free, without affecting the cereals.
Mode of action of antibiotics in human is also related example of the aforementioned mechanism. Tetracycline, a potent antibiotic, is used by humans. It inhibits ribosomal protein synthesis of bacteria but not in the host i.e., human. This selectivity in action occurs as a result of favourable distribution of the drug.
Bacteria may concentrate the antibiotics on account of selective permeability of their cell walls whereas the human cells are incapable of concentrating the antibiotics. Consequently, the concentrated drugs adversely affect the process of protein synthesis in bacteria without any otherwise effect or such effects to host cell.
Barriers to translocation of a chemical may be present in economical species whereas the same may be absent in uneconomical species.
2. Selective Toxicity due to Differences in the Biotransformation Mechanisms:
Selective toxicity of chemicals may also be achieved owing to differences in the biotransformation processes. Biotransformation is a biocatalytic conversion of one form of toxicant into another form in the body of organisms. The toxicants may also be converted into more active forms otherwise known as bioactivation which may, in turn, increase the toxicity of chemical in one group of organisms, whereas, in other group of organisms the same chemical may be converted into inactive forms and the toxicity of parent compound is diminished.
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Thus, the chemical may become nontoxic to other group of organisms. The biotransformation of toxicant may also alter the translocation of the chemical, hence the toxicity.
Actually the biotransformation mechanisms may vary in relation to genetic variations. One chemical may be toxic to certain strains and, at the same time, may be nontoxic to some other strains of a species.
For instance, an antibiotic penicillin is not effective against certain strains of bacteria, particularly the gram-negative, because of the presence of an enzyme, penicillinase, which converts the antibiotic into inactive form. Similarly, malathion is ineffective against certain strains of houseflies and mosquitoes because they possess a specific enzyme (esterase) which biotransforms malathion into inactive form, which causes least toxic effects to these insects.
The various biotransformation reactions take place at different rates in different species which may cause selective toxicity of a chemical to one species without having such effect to the other Heath (1961) reported the significance of rates of biocatalytic activation and inactivation of organophosphate pesticides as determinants of their selective toxicity to insect pests. These pesticides cause toxicity by bringing the inhibition of AChE activity.
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The organophosphorus pesticides can be grouped into two types:
i. Those having P = S group, and
ii. Those having P = O group.
The pesticides having P = O group possess the ability to directly inhibit AChE activity, whereas those having P = S group are first oxidised into active form (i.e., P = O from) in order to cause inhibition of enzyme, by microsomal mixed function oxidases (MMFO). The activated derivatives are then hydrolysed into inactive form by some other enzymes (i.e., esterases). In the rates of oxidation and hydrolysis of indirect type of AChE inhibitors differ in different species.
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The species in which the rate of oxidation of OP compounds is rapid and the rate of hydrolysis is slow, the active form of compound may accumulate which may induce the toxicity of the chemical. On the other hand, in other species, if the rate hydrolysis is rapid in comparison to the first species, the activated form of chemicals is rapidly converted into inactive form, hence the toxicity is diminished.
In Fig. 20.1 biotransformation of Malathion i.e., O, O-dimethyl, S (1, 2-dicarbethoxyethyl) phosphordithioate and relative rates of various steps of biotransformation in insects and mammals has been represented. First and foremost Malathion is oxidised into an active form, malaoxon, which is then hydrolysed into inactive products. Malathion may also be directly converted into products by hydrolysis and binding. The rate of oxidation in insects is rapid whereas the rate of hydrolysis and binding is very slow.
Consequently, the active form (i.e., malaoxon) is accumulated in insects which kills them. On the other hand, the rates of oxidation, hydrolysis and binding are rapid in mammals, hence active form is rapidly converted into inactive products which cause no harm to mammals. Thus, Malathion is selectively toxic to insects, i.e. uneconomical species, while causing no harm to mammals which are economical species.
3. Selective Toxicity due to Presence or Absence of Receptors:
In case of preceding two mechanisms the selective toxicity is the function of active concentration of the chemical at specific sites; may be either different cells of an organism or different organisms. But in this mechanism all the cell or organisms are exposed to the same concentration and the toxicants are selective in their action due to existence or absence of receptors. The toxicants induce their effects on account of their interaction with certain receptors.
It is also known that owing to cytological and biochemical differences in different groups of organisms, the specific receptors may be present in some whereas the same may be absent in others. Thus a chemical may be toxic to one form of life possessing appropriate receptors, at the same it may be nontoxic to other organisms which are devoid of such receptors.
The organo-phosphorus and carbamate insecticides owe their toxicity by interacting with AChE. These toxicants are similar in structure with that of natural substrate, ACh. Hence, they have close affinity for enzyme and bind to its active site. This binding actually involves strong covalent bonding forces leading to almost irreversible AChE- toxicants complex.
Consequently, enzyme is not available for reaction with natural substrate, thereby normal neurophysiological function is impaired. Thus, these toxicants affect the nervous physiology without affecting other systems. In this way these substances reveal selective effects.
Some other toxicants are selectively toxic because they are sufficiently similar in geometry to normal enzyme substrate like those of OP and carbamate insecticides and compete with normal substrates for the active sites of enzymes in the body of animals.
These toxicants also occupy the active sites of enzymes much in the same manner that normal substrate occupies and thus the enzymes do not remain available for natural substrate(s). One of the example of such selectively toxic chemical is sodium fluroacetate.
In the body of organisms, it forms fluorocitrate by condensation with oxaloacetate. The fluorocitrate then competes with citrate and binds at the active site of an enzyme, aconitase, leading to its inhibition. Thus, the sodium fluoroacetate blocks the TCA cycle in tissues and alters the physiology of organisms, ultimately leading to their death.