Phosphorothionate insecticides

Chambers JE, Ma T, Boone JS, et al. 1994. Role of detoxication pathways in acute toxicity levels of phosphorothionate insecticides in the rat. Life Sci 54 1357-1364. 

Loos MA (1975) Phenoxyalkanoic acids. In Kemey PC, Kaufman DD (eds) Herbicides chemistry, degradation and mode of action, vol 1. Marcel Dekker New York, pp 1-128 Lovley DR (1993) Dissimilatory metal reduction. Annual Review of Microbiology 47 263-290 Macalady DL, Wolfe NL (1983) New perspectives on the hydrolytic degradation of the organo-phosphorothionate insecticide chloropyrifos. J Agric Food Chem 31 1139-1147 Macalady DL, Wolfe NL (1985) Effects of sediment sorption and abiotic hydrolysis. J Agric Food Chem 33 167-173... 

Many organosulfur compounds undergo biological oxidation at the sulfur atom to yield products which have pronounced physiological activity or serve as intermediates in generating bioactive compounds. Three examples are the lachrymating agent in onions ( ) (1), the oxo intermediate ( ) in metabolic desulfuration of phosphorothionate insecticides to form potent cholinesterase inhibitors (2), and the sulfoxides QJ produced on metabolism of thiocarbamate herbicides (3). 

Desulfuration. Replacement of sulfur by oxygen is known to occur in a number of cases, and the oxygenation of the insecticide parathion to give the more toxic paraoxon is a good example of this (Fig. 4.25). This reaction is also important for other phosphorothionate insecticides. 

Photooxidation of parathion also occurred on leaf surfaces (18), together with isomerization and other reactions. Fenitro-thion (j),O-dimethyl 0-3-methyl-4-nitrophenyl phosphorothionate) and other phosphorothionate insecticides behaved similarly (19). Some pesticides do not require external reagents for photodegradation on surfaces carbamate insecticides such as carbaryl (1-naphthyl li-methylcarbamate), aminocarb (4-dimethylamino-3-methylphenyl li-methylcarbamate), and mexacarbate (4-dimethylamino-... 

Sultatos LG, Shao M, Murphy SD. The role of hepatic hiotransfoimation in mediating the acute toxicity of the phosphorothionate insecticide chlorpyrifos. Toxicol Appl Pharmacol 1984 73 60-8. 

Levine, B. and Murphy, S.D. 1977. Effects of piperonyl butoxide on the metabolism of dimethyl and diethyl phosphorothionate insecticides. Toxicol. Appl. Pharmacol., 40, 393-406. 

Reduction of the toxicity of the phosphorothionate insecticide, EPN, to rats by nikethamide [135] is paralleled by a reduction in the cholinesterase inhibitory potency of this compound in vivo [136]. Nikethamide induces the synthesis of oxidative microsomal enzymes [137] concerned in the detoxication of EPN in both male and female rats [138]. Induction of these enzymes by the daily administration of phenobarbitone, 50 mg/kg for 5 days, reduces the acute toxicities of parathion, demeton-0, EPN, disulfoton, dioxathion. 

A number of chemicals are metabolized in various species by desulfuration. In the case of the phosphorothionate insecticides, exchange of the sulfui for oxygen is an important step in the process of drug activation. The reaction has been shown to occur in mammals, fish, insects, and plants [20, 35, 36]. Murphy and Dubois [35] have also shown a sex-related metabolic difference in rats. 

One non-anticholinesterase effect of OPs has been discussed in section 10.3.1.3, namely OPIDP. The degree to which non-acetylcholinesterase inhibition effects contribute to acute OP toxicity continues to be a matter of interest and has been reviewed. Thus, Chambers " noted a poor correlation between rat oral LD50 values of various phosphorothionate insecticides and inhibition potency of corresponding oxons for brain acetylcholinesterase. However, there are a number of possible explanations for this, other than differences in target molecule notably, differences in site and magnitude of desulfuration of the thionate to the active oxon may be important. Studies by Duysen and colleagues with acetylcholinesterase knockout mice suggested that non-acetylcholinesterase inhibitory effects must contribute to the acute toxicity of VX. Maxwell et... 

This process of aging is believed to be critical in the development of delayed neuropathy, after NTE has been phosphorylated by an OP (see Chapter 10, Section 10.2.4). It is believed that most, if not all, of the B-esterases are sensitive to inhibition by OPs because they, too, have reactive serine at their active sites. It is important to emphasize that the interaction shown in Fignre 2.11 occurs with OPs that contain an oxon group. Phosphorothionates, which contain instead a thion group, do not readily interact in this way. Many OP insecticides are phosphorothionates, but these need to be converted to phosphate (oxon) forms by oxidative desulfuration before inhibition of acetylcholinesterase can proceed to any significant extent (see Section 2.3.2.2). 

Casida, J.E. and LJ. Lawrence. 1985. Structure-activity correlations for interactions of bicyclophosphorus esters and some polychlorocycloalkane and pyrethroid insecticides with the brain-specific t-butylcyclo-phosphorothionate receptor. Environ. Health Perspec. 61 123-132. 

The active constituent of this insecticide is stated to be 00 -diethyl 0"-ethylmercaptoethyl phosphorothionate,... 

It was shown that systox indeed consisted of 00 diethyl (S-ethylmercaptoethyl phosphorothiolate (VIII) and OO -di-ethyl O -ethylmercaptoethyl phosphorothionate (VII). (Compound (IX) was not present, and in any case it does not seem to have been fully characterized.) It seems that at room temperature (VII) isomerizes to (VIII), the half-life being about 3 years. Furthermore, the P=S compound is much less effective than the P=0 compound as an insecticide. 

Among phosphorus insecticides containing also nitrogen and sulphur we may mention 00 -diethyl-/S-/ -diethylaminoethyl phosphorothiolate (X). It was prepared (i) from diethyl phos-phorochloridate1 and sodium / -diethylaminoethyl mercaptide, (ii) from sodium diethyl phosphite and / -diethylaminoethyl thiocyanate, (iii) by the isomerization of OO -diethyl-O"-/ -diethylaminoethyl phosphorothionate (XI) obtained from / -diethylaminoethoxide and diethyl phosphorochloridothionate. 

The discovery of prontosil was fortuitous and was not based on rationale design. There are a large number of pesticides which fall in the same category as prontosil, i.e., they are active by virtue of their susceptibility to metabolic or chemical modification to active intermediates. The classical example of an insecticide of this type is parathion, a phosphorothionate ester which in animals or plants is oxidatively desulfurated to the potent anticholinesterase paraoxon O). The insecticidal activity of parathion was known for several years before the purified material was shown to be a poor anticholinesterase and that metabolic activation to paraoxon was necessary for intoxication. 

One of the most extensively studied phosphorothionate esters from the standpoint of mammalian metabolism is the insecticide parathion. The majority of this paper will center on what is known of the mechanism of mammalian microsomal metabolism of this compound. 

Parathion is one of a class of phosphorothionate triesters widely used as insecticides. These compounds exert their toxic effects in insects and mammals by inhibiting the enzyme acetylcholinesterase. The phosphorothionates, in general, are relatively poor inhibitors of acetylcholinesterase but are converted by the cytochrome P-450-containing monooxygenase enzyme systems in insects and mammals to the corresponding phosphate triesters that are potent inhibitors of this enzyme. 

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. 

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... 

Figure 17.6 General formulas and specific examples of phosphorothionate and phosphorodithioate organo-phosphate insecticides.

An example of a simple phosphorothionate is tributylphosphorothionate, in which the R groups (above) are n-CJ 1, groups. It is a colorless liquid (bp, 143°C). The compound is a cholinesterase inhibitor, as are some of its metabolic products. Examples of phosphorothionate and phosphorodithioate esters with more complex formulas synthesized for their insecticidal properties are discussed in the following section. 

Figure 18.9 gives the structural formulas of some typical phosphorothionate esters and the general formula of this type of organophosphate insecticide. 

Insecticidal parathion is a phosphorothionate ester first licensed for use in 1944. Pure parathion is a yellow liquid that is insoluble in kerosene and water, but stable in contact with water. Among its properties that make parathion convenient to use as an insecticide are stability in contact with neutral and somewhat basic aqueous solutions, low volatility, and toxicity to a wide range of insects. It was applied as an emulsion in water, dust, wettable powder, or aerosol. Even before it was banned for general use, it was not recommended for applications in homes or animal shelters because of its toxicity to mammals. 

Highly purified phosphorothionate and phosphorodithioate insecticides do not inhibit acetylcholinesterase directly. In order for these compounds to inhibit acetylcholinesterase, the following phase I metabolic conversion of P=S to P=0 must occur ... 

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