AOPs Including This Stressor
|Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function||High|
Events Including This Stressor
|Acetylcholinesterase (AchE) Inhibition|
|User term||DTXID||Preferred name||Casrn||jchem_inchi_key||indigo_inchi_key|
|Pinacolyl methylfluorophosphonate||DTXSID2031906||Pinacolyl methylphosphonofluoridate||96-64-0||GRXKLBBBQUKJJZ-UHFFFAOYNA-N||GRXKLBBBQUKJJZ-UHFFFAOYSA-N|
As mention in the AOPwiki “events/12” describing how organophoshate compounds initiate MIEs. The MIE and AChE inhibition is activated by electrostatic interaction at the anionic site of enzyme and binding with the serine hydroxyl radicals at esteratic site of AChE (Wilson 2010; Fukuto 1990). Phosphorylation of enzyme plays an important role in irreversible attachment of organophosphate pesticides to the AChE. The organophosphate has undergone a week long aging process “dealkylation” thus strengthening the bond among the OP and the enzyme (Sogob and Vilanova 2002). Organophosphate requires an electronegative leaving group for the formation of reactive electrophile to inhibit AChE (Fukuto 1990; Sogob and Vilanova 2002; Schuurmann 1992). Elements with minor difference in structure can result in major changes in AChE inhibition capabilities. For instance, If OPs having identical R and R1 alkyl groups which result in decrease of AChE inhibition as the R / R1 carbon chain increases from a single carbon to a propyl moiety, which causes ineffective AChE inhibition (Fukuto 1999). Metabolism can also play a major role in the effective inhibition of AChE. Organophosphates of the phosphorothionate and phosphorodithioate families require metabolic activation by cytochrome P450-based monoxygenases, to an oxon form to inhibit AChE efficiently (Fukuto 1990). Evidence support that undeveloped mammals and birds may be more sensitive to organophosphate pesticides depending to amount of pesticides ingestion to their body size (Ludke et al, 1975), data in rats showing that differential sensitivity to OPs is determined by inadequate detoxification in the young (Moser, 2011). OP detoxification in young is greatly dependent on lower level of enzymes such as A-esterases (paraoxonases, PON) and carboxylesterases (Furlong CE, 2007; Moser, 2011).
The MIE, AChE inhibition, is triggered via electrostatic interaction at the anionic site of the enzyme and binding with the serine hydroxyl group at the esteratic site of AChE (Wilson 2010; Fukuto 1990). Organophosphate pesticides attach to the AChE via an ‘irreversible’ phosphorylation of the enzyme. Note that the use of the term ‘irreversible’ relates to the relative rate at which the phosphorylation occurs since acetylcholine and organophosphates both form covalent bonds with the enzyme. The phosphorylated form may persist for up to a week if it has undergone an ‘aging’ process; i.e., the organophosphate has undergone a dealkylation, thereby strengthening the bond between the OP and the enzyme (Mileson et al. 1998; Kropp and Richardson 2003; Sogob and Vilanova 2002). Certain steric and electronic requirements must be met in order for an organophosphate to inhibit AChE. For instance, organophosphates require a leaving group sufficiently electronegative to ensure the formation of a reactive electrophile (Fukuto 1990; Sogob and Vilanova 2002; Schűűrmann 1992). Substances with subtle structural differences can result in major changes in AChE inhibition capabilities. For example, OPs having identical R and R1 alkyl groups display decreasing AChE inhibition as the R / R1 carbon chain increases from a single carbon to a propyl moiety, with the latter resulting in an ineffective AChE inhibitor (Fukuto 1999).
Metabolism also plays an important role in the potency of organophosphates. For instance, organophosphates in the phosphorothionate and phosphorodithioate families (i.e., P=S) must undergo metabolic activation, via cytochrome P450-based monoxygenases, to an oxon form in order to inhibit AChE effectively (Fukuto 1990).
Base Structure (OP)
R: A simple alkyl (e.g., methyl or ethyl group) or aryl group bonded to either an oxygen or sulfur that is directly bonded to the phosphorous;
R1: Methoxy, ethoxy, ethyl, phenyl, amino, substituted amino, or alkylthio group;
X: Leaving group that is or contains an electronegative moiety (e.g., phenoxy or aromatic group containing hetero atoms, substituted thioalkyl, or substituted alkoxy groups);
O: Oxons are direct acting
S: Thiophosphates require metabolic activation to the oxon form in order to be active AChE inhibitors
Evidence exists that immature life stages in mammals and birds may be more sensitive to organophosphate pesticides (see Grue et al., 1997; Grue et al., 1983; Grue et.al; 1981). It has been suggested that this may be related to the amount of pesticide ingested in relation to body size (Ludke et al, 1975), but there is direct data in rats showing that differential sensitivity to OPs is determined at least in part by inadequate detoxification in the young (Moser, 2011). OP detoxification is highly dependent on enzymes such as A-esterases (paraoxonases, PON) and carboxylesterases (e.g., Benke and Murphy, 1974; Furlong, 2007; Sterri et al., 1985; Vilanova and Sogorb, 1999), which are present at lower levels in the young (e.g., Chanda et al., 2002; Mendoza, 1976; Mortensen et al., 1996; Moser et al., 1998).
Characterization of Exposure
Collombet JM, Four E, Fauquette W, Burckhart MF, Masqueliez C, Bernabe D, Baubichon D, Lallement G (2007) Soman poisoning induces delayed astrogliotic scar and angiogenesis in damaged mouse brain areas. Neurotoxicology 28: 38-48
Zurich MG, Honegger P, Schilter B, Costa LG, Monnet-Tschudi F (2004) Involvement of glial cells in the neurotoxicity of parathion and chlorpyrifos. Toxicol Appl Pharmacol 201: 97-104