Preparation, analysis and anticholinesterase properties of O,O-dimethyl phosphorothioate isomerides

Thompson, Charles M.; Frick, J; Natke, Barbara; Hansen, Linda K.

doi:10.1021/tx00012a006

Cited by 47 publications

(37 citation statements)

References 29 publications

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“…The sulfur originally present in diazinon was lost. The source of the diethoxyphosphate adduct at 3064.5 amu can be rationalized by invoking a thiono-thiolo rearrangement in which the double bonded sulfur on the phosphorus atom is exchanged with the oxygen on the pyrimidinol ring (Thompson et al, 1989; Barr et al, 2005). The rearranged isomer structure, S-pyrimidine O,O-diethylphosphate, is shown in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Methamidophos, dichlorvos, O‐methoate and diazinon pesticides used in Turkey make a covalent bond with butyrylcholinesterase detected by mass spectrometry

Tacal

Lockridge

2010

J of Applied Toxicology

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Organophosphorus pesticides used most commonly in Turkey include methamidophos, dichlorvos, O-methoate, and diazinon. These toxic chemicals or their metabolites make a covalent bond with the active site serine of butyrylcholinesterase. Our goal was to identify the adducts that result from the reaction of human butyrylcholinesterase with these pesticides. Highly purified human butyrylcholinesterase was treated with a 20-fold molar excess of pesticide. The protein was denatured by boiling and digested with trypsin. MS and MSMS spectra of HPLC-purified peptides were acquired on a MALDI-TOF-TOF 4800 mass spectrometer. It was found that methamidophos added a mass of +93, consistent with addition of methoxy aminophosphate. A minor amount of adduct with an added mass of +109 was also found. Dichlorvos and O-methoate both made dimethoxyphosphate (+108) and monomethoxyphosphate adducts (+94). Diazinon gave a novel adduct with an added mass of +152 consistent with diethoxythiophosphate. Inhibition of enzyme activity in the presence of diazinon developed slowly (15 h), concomitant with isomerization of diazinon via a thiono-thiolo rearrangement. The isomer of diazinon yielded diethoxyphosphate and monoethoxyphosphate adducts with added masses of +136 and +108. MSMS spectra confirmed that each of the pesticides studied made a covalent bond with serine 198 of butyrylcholinesterase. These results can be used to identify the class of pesticides to which a patient was exposed.

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Section: Resultsmentioning

confidence: 99%

Methamidophos, dichlorvos, O‐methoate and diazinon pesticides used in Turkey make a covalent bond with butyrylcholinesterase detected by mass spectrometry

Tacal

Lockridge

2010

J of Applied Toxicology

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“…The effi cient CE-catalyzed detoxifi cation reaction has been studied by using MAL as preferential substrate: the reaction competes with the CYP-catalyzed formation of MAL oxon (Thompson et al, 1989;Sultatos, 1994) which is not hydrolyzed by PON1. Kinetic characterization with a panel of HLMs showed that either CE-catalysed or CYP-catalysed reactions consist of two components, highly differing in their affi nity for the pesticide (Buratti et al, 2005;Buratti and Testai, 2005a).…”

Section: Opt Detoxifi Cationmentioning

confidence: 99%

The Human Metabolism of Organophosphorothionate Pesticides: Consequences for Toxicological Risk Assessment

2007

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List of abbreviations: AChE = acetylcholinesterase; ADRs = adverse drug reactions; AZIN = azinphos-methyl; CE = carboxylesterases; Cli = intrinsic clearance; CPF = chlorpyrifos; CYP = cytochrome P450; DIA = diazinon; DIM = dimethoate; FEN = fenthion; FMO = fl avin-containing mono-oxigenase; IMI = imipramine; Iso-MAL = isomalathion; MAL = malathion; OP = organophosphorus compounds; OPT = organophosphorothionates; PAR = parathion; PON1 = oxonases.Abstract: Organophosphorothionates (OPT) are one of the most widely used insecticides in the world, both in agriculture and in indoor environment. Therefore, a large part of the population may be exposed to this class of pesticides, either professionally or due to their presence in food and water as residues. OPTs acute toxic effects, mediated by acetylcholinesterase (AChE) inhibition, are relatively selective to insects. However, most of the thousands of deaths annually reported to be associated to pesticide exposure are due to OPT severe poisoning, resulting in hyperexcitability of the nervous system. In addition, long-term neurological and neurobehavioral effects have been described, associated to chronic exposure to OPT low levels. Metabolism is one of the main factors determining OPT adverse effects. OPTs need to be bioactivated by a cytochrome P450 (CYP)-mediated desulfuration to phosphate triesters or oxons, which are the actual powerful inhibitors of brain and serum AChE. The main detoxifi cation pathways are oxon hydrolysis catalyzed by plasma oxonases (PON1), 'sequestration' or hydrolysis by carboxylesterases, CYP-catalyzed dearylation/dealkylation. Variation activity of the enzymes involved in OPT metabolism could be expected to contribute to differences in susceptibility to OPT toxic effects, either due to genetic polymorphism or environmental infl uence, altering the bioactivation/detoxication ratio. The reactions involved in OPT metabolism in humans are described in the paper, with consequences for OPT-induced toxicity. In addition, identifi cation of biomarkers of susceptibility and interactions among different OPTs and with other xenobiotics are briefl y discussed, as factors infl uencing risk assessment of cumulative effects due to OPT exposure.

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“…Malathion toxicity, in a manner similar to all OPTs, depends on its bioactivation to the toxic metabolite malaoxon (Thompson et al, 1989;Sultatos, 1994), which inhibits acetylcholinesterase (AChE) (Forsyth and Chambers, 1989), causing the accumulation of acetylcholine within synapses and the consequent overstimulation of postsynaptic receptors. Impurities, such as isomalathion and various trimethylphosphorothioate esters, present in the technical grade malathion or formed during storage, can potentiate malathion-induced toxicity up to 10-fold (Pellegrini and Santi 1972;Aldridge et al, 1979) and have been considered responsible for other effects, including DNA lesions (Flessel et al, 1993;Blasiak et al, 1999).…”

mentioning

confidence: 99%

Malathion Bioactivation in the Human Liver: The Contribution of Different Cytochrome P450 Isoforms

Buratti

D'Aniello²,

Volpe³

et al. 2004

Drug Metab Dispos

104

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ABSTRACT:Among organophosphorothioate (OPT) pesticides, malathion is considered relatively safe for use in mammals. Its rapid degradation by carboxylesterases competes with the cytochrome P450 (P450)-catalyzed formation of malaoxon, the toxic metabolite. However, impurities in commercial formulations are potent inhibitors of carboxylesterase, allowing a dramatic increase in malaoxon formation. Malathion desulfuration has been characterized in human liver microsomes (HLMs) with a method based on acetylcholinesterase inhibition that is able to detect nanomolar levels of oxon. The active P450 isoforms have been identified by means of a multifaceted strategy, including the use of cDNA-expressed human P450s and correlation, immunoinhibition, and chemical inhibition studies in a panel of phenotyped HLMs. HLMs catalyzed malaoxon formation with a high level of variability (>200-fold). One or two components (K mapp1 ‫؍‬ 53-67 M; K mapp2 ‫؍‬ 427-1721 M) were evidenced, depending on the relative specific P450 content. Results from different approaches indicated that, at low malathion concentration, malaoxon formation is catalyzed by CYP1A2 and, to a lesser extent, 2B6, whereas the role of 3A4 is relevant only at high malathion levels. These results are in line with those found with chlorpyrifos, diazinon, azynphos-methyl, and parathion, characterized by the presence of an aromatic ring in the molecule. Since malathion has linear chains as substituents at the thioether sulfur, it can be hypothesized that, independently from the chemical structure, OPTs are bioactivated by the same P450s. These results also suggest that CYP1A2 and 2B6 can be considered as possible metabolic biomarkers of susceptibility to OPT-induced toxic effects at actual human exposure levels.

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Preparation, analysis and anticholinesterase properties of O,O-dimethyl phosphorothioate isomerides

Cited by 47 publications

References 29 publications

Methamidophos, dichlorvos, O‐methoate and diazinon pesticides used in Turkey make a covalent bond with butyrylcholinesterase detected by mass spectrometry

Methamidophos, dichlorvos, O‐methoate and diazinon pesticides used in Turkey make a covalent bond with butyrylcholinesterase detected by mass spectrometry

The Human Metabolism of Organophosphorothionate Pesticides: Consequences for Toxicological Risk Assessment

Malathion Bioactivation in the Human Liver: The Contribution of Different Cytochrome P450 Isoforms

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