Phosphorothionates metabolism

Three different pathways are associated with the metabolism of disulfoton (I) oxidation of the thioether sulfur to produce sulfoxides and sulfones (2) oxidation of the thiono sulfur to produce the oxygen analogs and (3) hydrolysis of the P-S-C linkage to produce the corresponding phosphorothionate or phosphate (WHO 1976) (see Figure 2-3). These pathways have been elucidated from data obtained in humans exposed to disulfoton and from in vivo and in vitro metabolism studies in rats and mice. 

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. 

Chemical Mechanisms of the Cytochrome P-450 Monooxygenase-Catalyzed Metabolism of Phosphorothionate Triesters... 

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. 

Figure 3. Chemical mechanism for the metabolism of parathion to diethyl phosphorothionate and diethyl phosphate by the Cytochrome P-450-containing monooxygenase system (6)...

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. 

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). 

Contents Low-molecular-weight organosulfur compounds in nature / Eric Block—Chemical mechanisms of the cytochrome P-450 monooxygenase-catalyzed metabolism of phosphorothionate triesters / R. A. Neal —Sulfur in propesticide action / T. R. Fukuto and M. A. H. Fahmy—[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... 

Inhibition of the cholinesterase enzymes depends on blockade of the active site of the enzyme, specifically the site that binds the ester portion of acetylcholine (Fig. 7.48). 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. 

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. 

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 ... 

Dimethoate is rapidly absorbed after any route of administration in mammals. It is rapidly metabolized in the liver. Like other phosphorothionate pesticides, the parent compound is activated by cyp450 to... 

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. 

Halpert, X, D. Hammond, and R.A. Neal (1980). Inactivation of purified rat liver cytochrome P-450 during the metabolism of parathion (diethyl ju-nitro-phenyl phosphorothionate). J. Biol. Chem. 255, 1080 1089. 

The metabolism of dialkylaryl phosphorothionates by cow, rat and insect tissues may proceed by cleavage of both the alkyl phosphate and aryl phosphate bonds [150]. 

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