Malaoxon malathion metabolism

It Is well known that phosphorothlonate insecticides such as parathlon (, 0-diethyl p-nitrophenyl phosphorothloate) and malathion [0, -dimethyl -(l,2 -dlcarbethoxy)ethyl phosphoro-dithioate] are Intrinsically poor inhibitors of acetylcholinesterase and in vivo activation to the respective anticholinesterases paraoxon and malaoxon is required before animals exposed to the phosphorothionates are intoxicated. Since metabolic activation is essential to the biological activity of these thiono sulfur-containing organophosphorus insecticides, compounds of this type may be considered as propesticides or, more specifically, prolnsectlcldes. 

Esterase activity is important in both the detoxication of organophosphates and the toxicity caused by them. Thus brain acetylcholinesterase is inhibited by organophosphates such as paraoxon and malaoxon, their oxidized metabolites (see above). This leads to toxic effects. Malathion, a widely used insecticide, is metabolized mostly by carboxylesterase in mammals, and this is a route of detoxication. However, an isomer, isomalathion, formed from malathion when solutions are inappropriately stored, is a potent inhibitor of the carboxylesterase. The consequence is that such contaminated malathion becomes highly toxic to humans because detoxication is inhibited and oxidation becomes important. This led to the poisoning of 2800 workers in Pakistan and the death of 5 (see chap. 5 for metabolism and chap. 7 for more details). 

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). 

Liver metabolism and toxicity of the phosphorothioate insecticides parathion, guthion, and malathion were studied in several mammalian, avian, and piscine species (Murphy, 1966). As shown in Table 9.3 and 9.4, some species, such as the rat, produced the oxon (e.g., malaoxon) more slowly and degraded it more rapidly, whereas in others, such as the sparrow, the opposite is true. 

From a toxicological point of view, the induction of CarbEs may protect against the toxic effects of an ester if the compound itself is directly responsible for the toxic action (e.g., the reduced toxicity of malathion or malaoxon following hexachloroben-zene exposure in rats). Conversely, the induction of CarbE may potentiate the toxic effects produced by the hydrolytic products of the compound (e.g., in the metabolism of allyl alcohol). 

In fish the conversion of malathion to malaoxon is the dominant metabolic process, increasing the brain acetylcholinesterase-inhibiting potency a thousandfold (Murphy et al., 1968). Coppage et al. (1975) found inhibition of fish brain acetylcholinesterase suitable for the detection of environmental poisoning by malathion. 

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