Selective toxicity malathion

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

The onset of symptoms depends on the particular organophosphorus compound, but is usually relatively rapid, occurring within a few minutes to a few hours, and the symptoms may last for several days. This depends on the metabolism and distribution of the particular compound and factors such as lipophilicity. Some of the organophosphorus insecticides such as malathion, for example (chap. 5, Fig. 12), are metabolized in mammals mainly by hydrolysis to polar metabolites, which are readily excreted, whereas in the insect, oxidative metabolism occurs, which produces the cholinesterase inhibitor. Metabolic differences between the target and nontarget species are exploited to maximize the selective toxicity. Consequently, malathion has a low toxicity to mammals such as the rat in which the LD50 is about 10 g kg-1. 

Carboxylesterases are responsible for the selective toxicity of malathion that favors mammals over insects. Carboxylesterase hydrolyzing trans-permethrin has been found in numerous insect species, including the fall armyworm, velvetbean caterpillar (Anticar-sia gemmatalis), cabbage looper (Trichoplnsia ni), tobacco budworm (Heliothis virescens), corn earworm (Helicoverpa zea), and spined soldier bug (Podisus maculwentris) (Yu, 1990). 

A good example of selective toxicity is illustrated in Figure 9.11. Malathion is a weakly active insecticide, whereas malaoxon is a strongly active insecticide. One of the main reasons why malathion is highly toxic to insects but not to mammals is that the latter have high carboxylesterase activities, which rapidly attack the two carboxylesters, but the... 

Fig. 23. Malathion highly toxic to insects, less toxic to mammals. Note the high capacity to hydrolyse the carboxy ester moiety in mammals as compared to that in insects results in a selective toxicity for the latter...

This example illustrates two important points. First, malathion is a selectively toxic compound in that it kills insects without harming humans. Second, different species may metabolise drugs in different ways and extreme care must be exercised when extrapolating results from one species to another, notably from animal toxicity data to humans. 

The selective toxicity of malathion for insects is due in part to the low carboxyesterase activity in the insect as compared with the higher activity in mammals [62]. The differential rates of sulfur removal to produce an active metabolite also varies in insects and animals, which allows for further exploitation of metabolic differences. An additional reason for this selective toxicity for insects is the relatively greater amount of insecticide retained by the insect due to its large surface area (per unit weight) as compared to that of the mammal [63]. 

The development of malathion in 1950 was an important milestone in the emergence of selective insecticides. Malathion is from one-half to one-twentieth as toxic to insects as parathion but is only about one two-hundredths as toxic to mammals. Its worldwide usage in quantities of thousands of metric tons in the home, garden, field, orchard, woodland, on animals, and in pubHc health programs has demonstrated substantial safety coupled with pest control effectiveness. The biochemical basis for the selectivity of malathion is its rapid detoxication in the mammalian Hver, but not in the insect, through the attack of carboxyesterase enzymes on the aUphatic ester moieties of the molecule. 

In addition to ester bonds with P (Section 10.2.1, Figures 10.1 and 10.2), some OPs have other ester bonds not involving P, which are readily broken by esteratic hydrolysis to bring about a loss of toxicity. Examples include the two carboxylester bonds of malathion, and the amido bond of dimethoate (Figure 10.2). The two carboxylester bonds of malathion can be cleaved by B-esterase attack, a conversion that provides the basis for the marked selectivity of this compound. Most insects lack an effective carboxylesterase, and for them malathion is highly toxic. Mammals and certain resistant insects, however, possess forms of carboxylesterase that rapidly hydrolyze these bonds, and are accordingly insensitive to malathion toxicity. 

Amidases can be found in all kinds of organisms, including insects and plants [24], The distinct activities of these enzymes in different organisms can be exploited for the development of selective insecticides and herbicides that exhibit minimal toxicity for mammals. Thus, the low toxicity in mammals of the malathion derivative dimethoate (4.44) can be attributed to a specific metabolic route that transforms this compound into the nontoxic acid (4.45) [25-27]. However, there are cases in which toxicity is not species-selective. Indeed, in the preparation of these organophosphates, some contaminants that are inhibitors of mammalian carboxylesterase/am-idase may be present [28]. Sometimes the compound itself, and not simply one of its impurities, is toxic. For example, an insecticide such as phos-phamidon (4.46) cannot be detoxified by deamination since it is an amidase inhibitor [24],... 

Selective bioactivation (toxification) is illustrated in the case of the insecticide malathion (3.35). This acetylcholinesterase inhibitor is desulfurized selectively to the toxic malaoxon, but only by insect and not mammalian enzymes. Malathion is therefore relatively nontoxic to mammals (LDjg = 1500 mg/kg, rat p.o.). Higher organisms rapidly detoxify malathion by hydrolyzing one of its ester groups to the inactive acid, a process not readily available to insects. This makes the compound doubly toxic to insects since they cannot eliminate the active metabolite. 

Uncharged carbamates, such as carbaryl (8.20, sevin), can penetrate the CNS of insects (which do not use AChE in their neuromuscular junction) and they act quite selectively as insecticides with a low toxicity to mammals (median lethal dose [LDjg] in the rat = 540 mg/kg, p.o.). Many useful insecticides can thus be found in this group. Malathion (8.21) is a pro-drug, since the thiophosphate must be bioactivated to the phosphate form—a transformation carried out by insects but not mammals. Additionally, the ester groups of malathion are rapidly hydrolyzed in higher organisms to water-soluble and... 

Recall in our discussion of routes of biotransformation we considered species differences using malathion as an example. Insects convert this compound to its toxic oxidation product more quickly than they detoxify it by hydrolysis. Humans do the conversions in the opposite priority. However, the insects which might be different from the general population and perform detoxification reactions at a faster rate would survive pesticide application and their "resistant" genes would be selectively passed on to the next generations. 

The hydrolysis of esters by esterases and of amides by amidases constitutes one of the most common enzymatic reactions of xenobiotics in humans and other animal species. Because both the number of enzymes involved in hydrolytic attack and the number of substrates for them is large, it is not surprising to observe interspecific differences in the disposition of xenobiotics due to variations in these enzymes. In mammals the presence of carboxylesterase that hydrolyzes malathion but is generally absent in insects explains the remarkable selectivity of this insecticide. As with esters, wide differences exist between species in the rates of hydrolysis of various amides in vivo. Fluoracetamide is less toxic to mice than to the American cockroach. This is explained by the faster release of the toxic fluoroacetate in insects as compared with mice. The insecticide dimethoate is susceptible to the attack of both esterases and amidases, yielding nontoxic products. In the rat and mouse, both reactions occur, whereas sheep liver contains only the amidases and that of guinea pig only the esterase. The relative rates of these degradative enzymes in insects are very low as compared with those of mammals, however, and this correlates well with the high selectivity of dimethoate. 

Malathion has two carboxyester linkages, which are hydrolyzable by carboxylase enzymes to relatively nontoxic products, as shown in reaction 18.7.1. The enzymes that accomplish this reaction are possessed by mammals, but not by insects, so that mammals can detoxify malathion, whereas insects cannot. The result is that malathion has selective insecticidal activity. For example, although malathion is a very effective insecticide, its LD50 for adult male rats is about 100 times that of parathion, reflecting the much lower mammalian toxicity of malathion than those of some of the more toxic organophosphate insecticides, such as parathion. 

The well-known selectivities of some organophosphates may be explained by the balance of enzymatic events. The reduced toxicity of the insecticide malathion to mammals is largely the result of rapid activation by desulfuration in the insect and the more rapid detoxificaton by carboxylesterases and glutathione transferases in the mammal (3). Design of new pest bioregulators should exploit enhanced activation and decreased detoxification capabilities in the targeted pests. 

The organophosphosphates represent another extremely important class of organic insecticides. They were developed during World War II as chemical warfare agents. Early examples included the powerful insecticide schradan, a systemic insecticide, and the contact insecticide parathion. Unfortunately, both of these compounds are highly poisonous to mammals and subsequent research in this field has been directed toward the development of more selective and less poisonous insecticides. In 1950, malathion, the first example of a wide-specUnm organophosphorus insecticide combined with very low mammalian toxicity, was developed. And at about the same time the phenoxyacetic acid herbicides were discovered. These systemic compounds ate extremely valuable for the selective control of broad-leaved weeds in cereal crops. These compounds have a relatively low toxicity to mammals and are therefore relatively safe to use. 

Many pesticides are esters or amides that can be activated or inactivated by hydrolysis. The enzymes that catalyze the hydrolysis of pesticides that are esters or amides are esterases and amidases. These enzymes have the amino acid serine or cysteine in the active site. The catalytic process involves a transient acylation of the OH or SH group in serin or cystein. The organo-phosphorus and carbamate insecticides acylate OH groups irreversibly and thus inhibit a number of hydrolases, although many phosphorylated or carbamoylated esterases are deacylated very quickly, and so serve as hydrolytic enzymes for these compounds. An enzyme called arylesterase splits paraoxon into 4-nitrophenol and diethyl-phosphate. This enzyme has cysteine in the active site and is inhibited by mercury(ll) salts. Arylesterase is present in human plasma and is important to reduce the toxicity of paraoxon that nevertheless is very toxic. A paraoxon-splitting enzyme is also abundant in earthworms and probably contributes to paraoxon s low earthworm toxicity. Malathion has low mammalian toxicity because a carboxyl esterase that can use malathion as a substrate is abundant in the mammalian liver. It is not present in insects, and this is the reason for the favorable selectivity index of this pesticide. 

Dimethoate also has an intrinsic selectivity, for it is far more toxic to insects than to mammals. This favourable effect was found, surprisingly, to depend little on differences in S O conversion (as in malathion and diazinon), but to rely mainly on preferential operation of mammalian amidase (Krueger, O Brien and Dauterman, 1960). This discovery introduced an expanded feeling of latitude in designing selective organophosphate insecticides. 

Wong et al. [33] studied the enantiomeric composition of polychlorinated biphenyl (PCB) enantiomers in rivers from selected sites throughout the United States. Nonracemic enantiomeric fractions (EFs) were observed for PCBs 91, 95, 136 and 149 in aquatic samples. Bromocyclen, a new insecticide with a low toxicity to mammals, is currently in use in Europe for the treatment of domestic animals against ectoparasites. Therefore, bromocyclen has been reported in the waters of the Stor river, a tributary of the River Elbe in northern Germany [34-36]. Franke et al. [37] reported chlorinated bis(propyl)ethers in the waters of the River Elbe. Three isomers of bis(propyl)ethers have been reported in different parts of the river, and the authors identified an epichlorohydrin production site, close to the Czech border, as the source of this contamination. Many toxic pesticides, such as BHC, aldrin, dieldrin, DDT and so on, have been detected in the Yamuna River, which is a very important river in India [38], Similarly, DDT, BHC, aldrin, dieldrin, malathion and so on have also been detected in another very famous river, the Ganges [39]. Recently, Ali and Jain [40] have reported the presence of lindane, malathion, BHC, p,p -DDD, o,p -DDT and methoxychlor in the Hindon River, also in India. 

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