Carboxylesterases selective toxicity

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... 

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],... 

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. 

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. 

Wester RC, Bucks DAW, Maibach HI (1994) Human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide. Food Chem Toxicol 32 51-53 Wheelock CE, Wheelock AM, Zhang R, Stok JE, Morisseau C, Le Valley SE (2003) Evaluation of alpha-cyanoesters as fluorescent substrates for examining intraindividual variation in general and pyrethroid-selective esterases in human liver microsomes. Anal Bioehran 315 208—222 Wheelock CR, Miller JL, Miller MJ, Phillips BM, Huntley SA, Gee SJ, Tjeerdem RS, Hammock BD (2006) Use of carboxylesterase activity to remove pyrethroid-associated toxicity to Ceiiodaphnia dubia and Hyalella azteca toxicity in identification evaluations. Environ Toxicol Chem 25 973-984... 

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