Malathion hydrolysis

There are two types of esterases that are important in metabolizing insecticides, namely, carboxylesterases and phosphatases (also called phosphorotriester hydrolases or phosphotriesterases). Carboxylesterases, which are B-esterases, play significant roles in degrading organophosphates, carbamates, pyrethroids, and some juvenoids in insects. The best example is malathion hydrolysis, which yields both a- and (i-monoacids and ethanol (Figure 8.10). 

The enzymes that accomplish malathion hydrolysis are possessed by mammals, but not by insects, and so mammals can detoxify malathion and insects cannot. The result is that malathion... 

The enzymes that accomplish malathion hydrolysis are possessed by mammals, but not by insects, so mammals can detoxify malathion and insects caimot. The result is that malathion has selective insecticidal activity. For example, although malathion is a very effective insecticide, its LDjq (dose required to kill 50% of test subjects) for adult male rats is about 100 times that of parathion, reflecting the much lower mammalian toxicity of malathion compared with some of the more toxic organophosphate insecticides, such as parathion. 

The oxidation of OPs can bring detoxication as well as activation. Oxidative attack can lead to the removal of R groups (oxidative dealkylation), leaving behind P-OH, which ionizes to PO . Such a conversion looks superficially like a hydrolysis, and was sometimes confused with it before the great diversity of P450-catalyzed biotransformations became known. Oxidative deethylation yields polar ionizable metabolites and generally causes detoxication (Eto 1974 Batten and Hutson 1995). Oxidative demethy-lation (0-demethylation) has been demonstrated during the metabolism of malathion. 

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. 

The main purpose of this work is development of small-scale and mobile dsMmposition system of these chemicals. A number of studies on decomposition of organophosphorus insecticides have been conducted [1-3]. It is well known that or nophosphorus insecticides are decomposed by hydrolysis under alkaline condition, and its meciianisms have been studied [4], Even so, relatively few papers have address the devdopment of kinetic equations for reactor desipi. In this study, we aim to get kinetic equaticms for their decomposition under alkaline condition. As organophosphtous, we used parathion, fenitrothion, diazinon, malathion and phenthoate. 

The toxicity of an insecticide not only depends upon its molecular structure but also the way it is metabolised. A good example of this is Malathion (77), which is metabolised very differently by insects and humans and is therefore only toxic to insects. The mildly active Malathion (77) is rapidly oxidised in insects converting it into the strongly active oxidation product 79 (Equation 84), and this is only broken down very slowly by hydrolysis to give the weakly active 81. In contrast, oxidation of Malathion in mammals is slow, but hydrolysis of the ester group occurs very rapidly to give the inactive non-toxic compound 80 (Equation 84).1,169... 

Microorganisms can inactive toxicants by cleavage of a bond by the addition of water. Such reactions may involve a simple hydrolysis of an ester bond, as with the insecticide Malathion by a carboxyesterase enzyme ... 

Matsumura and Bousch (1966) isolated carboxy lest erase (s) enzymes from the soil fungus Trichoderma viride und a bacterium Pseudomonas sp., obtained from Ohio soil samples, that were capable of degrading malathion. Compounds identified included diethyl maleate, desmethyl malathion, carboxylesterase products, other hydrolysis products, and unidentified metabolites. The authors found that these microbial populations did not have the capability to oxidize malathion due to the absence of malaoxon. However, the major degradative pathway appeared to be desmethylation and the formation of carboxylic acid derivatives. 

Chemical/Physical. Hydrolyzes in water forming cis-diethyl fumarate, tra/ s-diethyl fumarate (Suffet et ah, 1967), thiomalic acid, and dimethyl thiophosphate (Mulla et al., 1981). The reported hydrolysis half-lives at pH 7.4 and temperatures of 20 and 37.5 °C were 10.5 and 1.3 d, respectively (Freed et al, 1977). In a preliminary study, Librando and Lane (1997) concluded that the hydrolysis of malathion is very sensitive to pH. At pH 8.5, <5% of the malathion remains after 2 d, whereas at pH 5.7, >90% remains after 20 d. 

When applied as an aerial spray, malathion was converted to malaoxon and diethyl fumarate via oxidation and hydrolysis, respectively (Brown et al, 1993). 

Bender, M.E. The toxicity of the hydrolysis and breakdown products of malathion to the fathead minnow (Pimephales promelas, Rafinesque), Water Res., 3(8) 571-582, 1969. 

It should be noted that hydrolysis of these pesticides is expected to occur simultaneously with volatilization for the pesticides studied (Table I). Over a 7 day experiment, however, only malathion and mevlnphos would be expected to hydrolyze to a significant extent. We determined the loss rate of mevlnphos to be 0.0016 0.0002 hr l (tjj = 18 days), and of malathion to be 0.011 0.001 hr-1 (t j = 2.6 days) at 22 2°C, at pH 8.2+0.2 for a model evaporation pond by daily sampling of duplicate pesticide solu-Xlons (covered to prevent volatilization) for 7 days and plotting log concentration versus time. For both of these pesticides, then, degradation was a much more important route of pesticide loss from water than volatilization. The relatively slow loss rate of the other pesticides could not be determined in our 7 day... 

The relative importance of the two processes in a model evaporation pond, along with the time lor 97% loss of the applied pesticide (system purification time), were calculated (Table V). This calculation confirmed that mevinphos and malathion dissipated primarily by hydrolysis, with malathion the more rapid of these two chemicals. For methyl and ethyl parathion, both processes were significant, although volatilization was the dominant dissipation route. However, since both processes were relatively slow for these pesticides, the purification time was fairly long. Diazinon was predicted to be lost primarily via volatilization, and the purification time was relatively short. 

The primary design parameter to be considered in hydrolysis is the half-life of the original molecule, which is the time required to react 50% of the original compound. The half-life is generally a function of the type of molecule hydrolyzed and the temperature and pH of the reaction. Figure 13 shows the elfect of pH and temperature for the degradation of malathion by hydrolysis [11]. 

Figure 13 Effect of pH and temperature on malathion degradation by hydrolysis (temperature in degrees C) degradation is faster at higher temperatures and pH values further away from 4.0 to 4.2 (from Ref. 11).

Irreversible cholinesterases are mostly organophosphorus compounds and combine only with esteratic site of cholinesterase and that site gets phosphorylated. The hydrolysis of phosphorylated site produces irreversible inhibition of cholinesterase. And, because, of this property, the therapeutic usefulness is very limited. Most of the compounds are used as insecticides e.g. parathion, malathion and war gases e.g. tabun, sarin, soman etc. 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

A rapid oxidation process in insects converts the relatively inocuous malathion to the toxic malaoxon. Detoxification by hydrolysis proceeds at much slower rate. Therefore the toxic species buildups up in the the insect and eventually kills it. However, in humans the process is reversed. The detoxifying hydrolysis reaction is faster that the toxifying oxidation. The result is an insecticide which can be used by humans with relative safety. 

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. 

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. 

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 term potentiation is then reserved for those cases where both compounds have appreciable intrinsic toxicity, such as in the case of malathion and EPN. Malathion has a low mammalian toxicity due primarily to its rapid hydrolysis by a carboxylesterase. EPN (Figure 9.6) another organophosphate insecticide, causes a dramatic increase in malathion toxicity to mammals at dose levels, which, given alone, cause essentially no inhibition of acetylcholinesterase. The increase in toxicity as a result of coadministration of these two toxicants is the result of the ability of EPN, at low concentrations, to inhibit the carboxylesterase responsible for malathion degradation. 

Diazinon, Parathion, Malathion, Fenthion and oxygen analyses and hydrolysis products Reoplex- 400 Electron capture flame ionisation [450]... 

Several human carboxylesterases have been cloned, sequenced and expressed. These human carboxylesterases are important in the hydrolysis of certain pesticides such as the pyrethroids. In certain strains of insects that are resistant to malathion, the resistance mechanism is associated with a higher level of a carboxylesterase, which detoxifies malathion (Figure 10.10D). 

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