Stereo-specific degradation of the R−(+) isomer of O-n-hexyl-S-methylphosphorothioamidate catalysed by rabbit serum

doi:10.1016/0009-2797(93)90034-V

Chemico-Biological Interactions

Volume 87, Issues 1–3, June 1993, Pages 133-139

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Abstract

Resolved isomers of O-n-hexyl-S-methylphosphorothioamidate (HXM) which had been synthesised by separate stereospecific routes were analysed by chiral glc: about 2–3% of R−(+) isomer was found in the S−(−) sample and accounted for nearly all the inhibitory power against neuropathy target esterase. Incubation of racemic HXM with rabbit serum led to slow but very specific disposal of R−(+) isomer to undetectable levels with very slight loss of S−(−): the rate of disposal was roughly estimated to be about 1% of the published rate of hydrolysis of paraoxon. Incubation with crystalline chymotrypsin caused a preferential but not totally selective disposal of S−(−) isomer.

References (6)

E. Vilanova et al.
Interaction of some unsubstituted phosphoramidate analogues of methamidophos (O,S-dimethyl phosphorothioamidate) with acetylcholinesterase and neuropathy target esterase of hen brain
Pestic. Biochem. Physiol.
(1987)
M.K. Johnson et al.
Biochemical and clinical tests of the delayed neuropathic potential of some O-alkyl O-2,5-dichlorophenyl analogues of methamidophos (O,S-dimethyl phosphorothioamidate)
Toxicology
(1989)
M.K. Johnson et al.
The R−(+) isomer of O-n-Hexyl S-methyl Phosphorothioamidate causes delayed neuropathy in hens after generation of a form of inhibited neuropathy target esterase which can be reactivated ex vivo
Chem.-Biol. Interact.
(1993)

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Cited by (8)

Stereospecific hydrolysis of a phosphoramidate as a model to understand the role of biotransformation in the neurotoxicity of chiral organophosphorus compounds
2007, Toxicology Letters
Calcium-dependent and EDTA-resistant hydrolyses of R and S isomers of O-hexyl O-2,5-dicholorophenyl phosphoramidate (HDCP) were observed in serum and subcellular fractions of liver, kidney and brain from hen, rat and rabbit. In serum, the Ca²⁺-dependent hydrolysis was much higher in rabbit than in other species. Liver showed a higher activity than kidney and brain. The S-HDCP isomer was hydrolysed to a higher extent than the other isomer. The fact that this stereospecificity favours the S-isomer is more clearly observed in rabbit serum, and in rat and rabbit liver particulate fractions. In such tissues and species, the EDTA-resistant hydrolysis was not stereospecific. Soluble fractions of rat brain and of hen liver, kidney and brain, showed a lower total activity but with a higher proportion of EDTA-resistant activity and a higher hydrolysis of the R-HDCP isomer. The Ca²⁺-dependent stereoselective biodegradation of S-HDCP is dominant in the most active tissues in rabbit and rat. It can therefore be concluded that S-HDCP would be biodegraded faster than R-HDCP. Furthermore, R-HDCP is the isomer that will remain at a higher proportion to be available for interaction with the target of neurotoxicity.
Toxicological assessment of isomeric pesticides: A strategy for testing of chiral organophosphorus (OP) compounds for delayed polyneuropathy in a regulatory setting
2004, Food and Chemical Toxicology
Many compounds, including some pesticides, contain structural centres of asymmetry, which convey the property of a type of stereoisomerism known as chirality. Such compounds can exist in two or more forms, depending on the number of chiral atoms and are termed stereoisomers or enantiomers. Stereoisomers of a particular compound can have different biological properties; one such of particular importance for toxicological evaluation, is the potential for differences in metabolic disposal of and binding of stereoisomers to molecular targets in the cell. The combination of differential metabolism of chiral organophosphorus (OP) pesticides and opposing stereoselectivity of inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE) can affect the value of the hen test, performed to OECD guidelines, in predicting the potential to cause organophosphate-induced delayed polyneuropathy (OPIDP) in humans. This is a mixed central and sensory and motor neuropathy. The experimental data on structural analogues of the pesticide methamidophos and the evidence for stereoselective OPIDP are reviewed and a model is given demonstrating how the properties of a chiral OP can result in the neuropathic potential not being detected by the standard hen test. A strategy for the assessment of a racemic mixture comprised of two OP enantiomers for the potential to induce OPIDP is outlined. The strategy uses information from structure activity relationships (SAR), in vitro tests and in vivo tests to allow risk assessment decisions to be made. It is suggested that the potential for stereoselective toxicity of pesticides should be routinely considered in regulatory assessments.
A stereospecific phosphotriesterase in hen liver and brain
1998, Chemico-Biological Interactions
O-Hexyl, O-2,5-dichlorophenyl phosphoramidate (HDCP) is a chiral compound that induces delayed neuropathy in hens. This compound is hydrolyzed by a phosphotriesterase known as HDCPase in hen and rat plasma, liver and brain. We studied the stereospecificity of HDCPase in hen tissues and in human and rabbit plasma employing a chromatographic method for analysis and quantification of HDCP stereoisomers. Hen and human plasma HDCPases were not stereospecific. However, rabbit plasma showed a remarkable stereospecificity to S-(−)-HDCP. High levels of stereospecific HDCPase were found in the particulate fraction of hen liver, where S-(−)-HDCP is hydrolyzed faster than R-(+)-HDCP. However, in hen brain the stereospecificity was found in the soluble fraction, where R-(+)-HDCP is hydrolyzed faster than S-(−)-HDCP. It is concluded that liver particulate fraction must be the main tissue responsible for the HDCP stereospecific biotransformation in hens. In an oral administration, the steroisomer R-(+)-HDCP would survive after passing through the liver and would interact with acetylcholinesterase and neuropathy target esterase in the nervous system.
Inhibition and aging of neuropathy target esterase by the stereoisomers of a phosphoramidate related to methamidophos
1997, Toxicology Letters
Discrepancies in the aging reaction between neuropathy target esterase (NTE) inhibited in vitro and in vivo by racemic mixtures of O-alkyl O-2,5-dichlorophenyl phosphoramidates have been observed. It suggested the existence of differences in the interactions (inhibition and aging) between NTE and each stereoisomers of the above mentioned compounds. In order to verify this hypothesis, stereoisomers of O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) were isolated by chiral column chromatography, followed by the evaluation of NTE inhibition and aging for each stereoisomers. The loss of reactivation capacity by KF was used as criterion of aging. The stereoisomer S-(−)-HDCP inhibited hen brain NTE with an I₅₀ of 7.6 nM for 30 min of incubation, this being similar to the value obtained for the racemic mixture (I₅₀=6.2 nM), and much lower than that recorded for R-(+)-HDCP (I₅₀=191 nM). NTE inhibited by HDCP racemic mixture and the stereoisomer S-(−)-HDCP was reactivated by KF after 20 h of incubation at 37°C. The NTE inhibited by R-(+)-HDCP could not be fully reactivated after inhibition.
The R-(+)isomer of O-n-hexyl S-methyl phosphorothioamidate causes delayed neuropathy in hens after generation of a form of inhibited neuropathy target esterase (NTE) which can be reactivated ex vivo
1993, Chemico-Biological Interactions
To initiate delayed neuropathy (DN) in adult hens organophosphates and phosphonates must inhibit most neural NTE and the inhibited NTE must undergo an ‘aging’ reaction. Phosphinates and those chiral isomers of phosphonates which produce non-aging NTE do not cause DN but act as prophylactic agents. Some racemic phosphoramidates cause DN although the inhibited NTE in autopsy samples can be reactivated in vitro (Johnson, Read and Vilanova, 1991, Arch. Toxicol., 65, 618–624). We now report that pure R(+) isomer of O-n-hexyl S-methyl phosphorothioamidate (5–20 mg/kg per os) caused slight acute effects but typical DN associated with high inhibition of NTE in brain, spinal cord and sciatic nerve (maximum by 6–24 h): the inhibited NTE was easily reactivated by KF (presumed not aged). For each dose the average residual NTE activity in the three tissues 24 h after dosing and the clinical ataxia severity on peak days 15–17 (score out of 4) was: 5 mg/kg: 13, 14, 27% (2,2,2,1); 10 mg/kg: 10,14,12%, (4,3,2); 15 mg/kg: 10,11,17%, (3,3,4); 20 mg/kg: 6, 10, 8%, (3,3,3,2). The ability of this isomer and of other racemic phosphoramidates to initiate DN by covalent reaction at the active site of NTE (inhibition) without subsequent aging suggests that the chemistry (? charge distribution) in the region of the phosphorus atom determines that disturbance in the molecular environment of NTE which initiates DN.
Hydrolysis of chiral organophosphorus compounds by phosphotriesterases and mammalian paraoxonase-1
2021, Frontiers in Bioscience - Landmark

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Chemico-Biological Interactions

Abstract

References (6)

Interaction of some unsubstituted phosphoramidate analogues of methamidophos (O,S-dimethyl phosphorothioamidate) with acetylcholinesterase and neuropathy target esterase of hen brain

Pestic. Biochem. Physiol.

Biochemical and clinical tests of the delayed neuropathic potential of some O-alkyl O-2,5-dichlorophenyl analogues of methamidophos (O,S-dimethyl phosphorothioamidate)

Toxicology

The R−(+) isomer of O-n-Hexyl S-methyl Phosphorothioamidate causes delayed neuropathy in hens after generation of a form of inhibited neuropathy target esterase which can be reactivated ex vivo

Chem.-Biol. Interact.

Cited by (8)

Stereospecific hydrolysis of a phosphoramidate as a model to understand the role of biotransformation in the neurotoxicity of chiral organophosphorus compounds

Toxicological assessment of isomeric pesticides: A strategy for testing of chiral organophosphorus (OP) compounds for delayed polyneuropathy in a regulatory setting

A stereospecific phosphotriesterase in hen liver and brain

Inhibition and aging of neuropathy target esterase by the stereoisomers of a phosphoramidate related to methamidophos

The R-(+)isomer of O-n-hexyl S-methyl phosphorothioamidate causes delayed neuropathy in hens after generation of a form of inhibited neuropathy target esterase (NTE) which can be reactivated ex vivo

Hydrolysis of chiral organophosphorus compounds by phosphotriesterases and mammalian paraoxonase-1