Organophosphorus Compounds

There are many different cholinesterase inhibitors which find use, particularly as insecticides but also as nerve gases for use in chemical warfare. Organophosphorus insecticides are the most widely used and the most frequently involved in fatal human poisonings. They may be absorbed through the skin and there have been accidental poisoning cases arising from such exposure. Accidental contamination of food with insecticides such as parathion has led to a significant number of deaths. There are two types of toxic effects: inhibition of cholinesterases and delayed neuropathy.

Cholinesterase inhibition

The inhibition of cholinesterases results in a number of physiological effects. The enzyme acetylcholinesterase, found in various tissues including the plasma, is responsible for hydrolysing acetylcholine. This effectively terminates the action of the neurotransmitter at the synaptic nerve endings which occur in the central nervous system and other tissues such as glands and smooth muscle. The inhibition leads to accumulation of acetylcholine, and therefore the signs of poisoning resemble excessive stimulation of cholinergic nerves. The toxicity becomes apparent when there is about 50% inhibition of acetylcholinesterase, and at 10-20% of normal activity death occurs. The toxic effects can be divided into three types as the accumulation of acetylcholine leads to symptoms which mimic the muscarinic, nicotinic and CNS actions of acetylcholine. Muscarinic receptors for acetylcholine are found in smooth muscles, the heart and exocrine glands. Therefore the signs and symptoms are tightness of the chest, wheezing due to bronchoconstriction, bradycardia and constriction of the pupils (miosis). Salivation, lacrimation and sweating are all increased, and peristalsis is increased leading to nausea, vomiting and diarrhoea.

Nicotinic signs and symptoms result from the accumulation of acetylcholine at motor nerve endings in skeletal muscle and autonomic ganglia. Thus, there is fatigue, involuntary twitching and muscular weakness which may affect the muscles of respiration. Hypertension and hyperglycaemia may also reflect the action of acetylcholine at sympathetic ganglia.

Accumulation of acetylcholine in the CNS leads to a variety of signs and symptoms including tension, anxiety, ataxia, convulsions, coma and depression of the respiratory and circulatory centres. The cause of death is usually respiratory failure due partly to neuromuscular paralysis, central depression and bronchoconstriction.

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 (figure 5.10), 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 non-target 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/

Mechanism of inhibition of cholinesterases

Inhibition of the cholinesterase enzymes depends on blockade of the active site of the enzyme, specifically the site which binds the ester portion of acetylcholine (figure 7.31). The organophosphorus compound is thus a pseudosubstrate. However, in the case of some compounds such as the phosphorothionates (parathion and malathion for example), metabolism is necessary to produce the inhibitor. In both cases metabolism by the microsomal mono-oxygenase enzymes occurs in which the sulphur atom attached to the phosphorus is replaced by an oxygen (figure 5.10).

With malaoxon the P=O group binds to a serine hydroxyl group at the esteratic site of the cholinesterase enzyme in an analogous manner to the C=O group in the normal substrate acetylcholine (figures 7.31 and 7.32). With acetylcholine the enzyme-substrate complex breaks down to leave acetylated enzyme, which is then rapidly hydrolysed to regenerate the serine hydroxyl group and hence the functional enzyme. With organophosphorus compounds such as malathion (figure 7.31), the bound organophosphorus compound also undergoes cleavage to release the corresponding thiol or alcohol, leaving phosphorylated enzyme. However, unlike the acetylated enzyme intermediate produced with acetylcholine, the phosphorylated enzyme is only hydrolysed very slowly, if at all. Consequently, the active site of the enzyme is effectively blocked. If the phosphorylated enzyme undergoes a change known as ageing in which one of the groups attached to the phosphorus atom is lost, then the inhibition may become more permanent. However, the toxicity will ultimately depend on the affinity of the enzyme for the inhibitor and the rate of hydrolysis of the phosphorylated intermediate. These will in turn depend on the nature of the substituent groups on the phosphorus atom (figure 7.32). Furthermore, the rates of metabolism to the active metabolite and via other routes will also be determinants of the toxicity.

Although a particular organophosphorus compound may be rapidly metabolized and therefore not accumulate in the animal, chronic dosing may cause a cumulative toxic effect due to the slow rate of reversal of the inhibition. Thus the rate of regeneration may be slow with a half-life of the order of 1030 days. Thus, in some cases resynthesis of the

FIGURE 7.31 Mechanism of hydrolysis of acetylcholine by acetylcholinesterase and blockade of the enzyme by malaoxon. With malaoxon as substrate, the final step, regeneration of the enzyme by hydrolysis, is blocked f leading to inactivated enzyme.

FIGURE 7.31 Mechanism of hydrolysis of acetylcholine by acetylcholinesterase and blockade of the enzyme by malaoxon. With malaoxon as substrate, the final step, regeneration of the enzyme by hydrolysis, is blocked f leading to inactivated enzyme.

ActfylcCnlincstcrasa Catalysis



FIGURE 7.32 General scheme for acetylcholinesterase action. R may=C or P. If R=P, then (R3) is present. The group OR1 may be replaced by SR}, giving

RjSH on hydrolysis (reaction 1). IFR=P, reaction 2 is very slow, giving inactivated enzyme. The rate of hydrolysis or reactivation depends on the nature of R2 and R3.

AcetylLhdi reslsrase

AcetylLhdi reslsrase

AcelytiidirxKlc^fso -1-. i

Serine OH

FIGURE 7.33 The mechanism of reaction of the antidote pralidoxime with phosphorylated acetylcholinesterase. The original acetylcholinesterase is thereby regenerated.

enzyme may be the limiting factor. Thus repeated, small non-toxic doses can cause eventual toxicity when sufficient of the cholinesterase is inhibited. Different cholinesterases have different half-lives. The acetylcholinesterases present in red blood cells, which is similar to that in the nervous tissue, remains inhibited after di-isopropylfluorophosphate for the lifetime of the red blood cell.

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  • Elisa Samuel
    Where and how organophosphorus compound metabolized?
    3 years ago

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