Hydrolysis selective toxicity

A few organophosphorus insecticides are also phosphoramidates, hydrolysis of the P-N bond being considered a route of detoxification. This is exemplified by the metabolism of acephate (9.82, Fig. 9.15), whose mechanisms of activation and detoxification have recently been re-examined in mice to better understand the relative innocuity of the compound in mammals and its selective toxicity in insects [156],... 

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. 

Figure 12.63 provides another example of the diversity of metabolic processes to which pesticides are subjected after application. In the case of the carbamate insecticide carbaryl, the predominant processes are oxidation and hydrolysis, which maybe followed by conjugation of primary metabolites with glutathione. The character of metabolic transformations is closely related to the pesticide selectivity (toxicity) to target and non-target organisms. 

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. 

There are six primary in-plant control methods for removal of priority pollutants and pesticides in pesticide manufacturing plants. These methods include steam-stripping, activated carbon adsorption, chemical oxidation, resin adsorption, hydrolysis, and heavy metals separation. Steam-stripping can remove volatile organic compounds (VOCs) activated carbon can remove semi volatile organic compounds and many pesticides and resin adsorption, chemical oxidation, and hydrolysis can treat selected pesticides [7]. Heavy metals separation can reduce toxicity to downstream biological treatment systems. Discussion of each of these methods follows. 

The phenoxy herbicides inexpensiveness, selectivity, nonpersistency and low toxicity to animals are difficult to beat. Application is usually accomplished by spraying on the leaves. The herbicides cannot themselves be applied to the soil because they are washed away or decomposed by microorganisms in a few weeks. They can be applied by this method using a sulfonic acid derivative that, after hydrolysis in the soil and oxidation by bacteria, can form 2,4-D in the plant. 2,4-D is still the main herbicide used on wheat. 

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. 

These results are clear evidence that sulfur reacts mainly directly with Pt amine compounds, substituting Cl-, without prior aquation. As is evident from Table IV, the hydrolyzed species [Pt(dien)(H20)]2+ will almost selectively react with 5 -GMP (3.6 Af-1 sec-1 versus 0.51 Af-1 sec-1 and 0.18 Af-1 sec-1), whereas the chloro species [Pt(dien)Cl]+ will only react with sulfur. This information is of extreme importance in the strategy of the development of new Pt drugs. If it would be possible to develop a compound with structural properties such that the direct attack by sulfur is inhibited, but with a similar rate of chloro hydrolysis compared to cis-Pt, this would lead to compounds with improved antitumor properties and lower toxicities. The data depicted in Table IV were obtained at pH 5. However, it has been proved that GS- reacts remark-... 

Perchloryl fluoride is thermally stable up to 500° C. and very resistant to hydrolysis. It is a colorless gas in ordinary conditions with b.p., —46.7°C., and m.p., —147.8°C. It is a powerful oxidant at elevated temperatures. It exhibits selective fluorination properties and has been used as a perchlorylation reagent for introducing the C103 group on carbon in organic compounds. It is moderately toxic (maximum allowable concentration, 3 p.p.m.8). A comprehensive review of the production, physical properties, and reactions of perchloryl fluoride is available.9... 

The chemical agents stored at the two bulk-only sites differ substantially (HD mustard agent at Aberdeen, Maryland, and VX nerve agent at Newport, Indiana). Therefore, different treatment process sequences were selected for use at the two sites. In both processes, the chemical bonds associated with agent toxicity will be destroyed by hydrolysis (with water for HD or aqueous sodium hydroxide for VX) (NRC, 1996a). However, in order to achieve rapid and... 

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. 

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