Malathion hydrolysis reactions

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. 

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 ... 

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]. 

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... 

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 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 (chemathion, mala-spray) requires conversion to malaoxon (replacement of a sulfur atom with oxygen in vivo, conferring resistance to mammalian species). Malathion can be detoxified by hydrolysis of the carboxyl ester linkage by plasma carboxylesterases, and plasma car-boxylesterase activity dictates species resistance to malathion. The detoxification reaction is much more rapid in mammals and birds than in insects. Malathion has been employed in aerial spraying of relatively populous areas for control of Mediterranean fruit flies and mosquitoes that harbor and transmit viruses harmful to human beings (e.g.. West Nile encephalitis virus). Evidence of acute toxicity from malathion arises only with suicide attempts or deliberate poisoning. 

Malathion has low mammalian toxicity and is widely used as an insecticide. It is informative to review the hydrolysis of this compound since both the thiophosphate and carboxylic ester components of the molecule would be susceptible. " The major product under acid conditions is the monoacid (two isomers are possible) with little involvement of the thiophosphate moiety (Reaction 1, Fig. 8.12). At pH 4, malathion would have a half-life of 4.5 years at 27°C. Since environmental pH values rarely are this low, the base-catalyzed process would be more relevant. Under these conditions, the carboxylic ester would hydrolyze (fen ), while an elimination reaction (kme) occurs with the thiophosphate ester splitting out H2S from the thiolsuccinate to... 

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