Environmental Engineering Reference
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Fig. 4 Diagrammatic representation of the mechanism of action of chlorpyrifos in the nerve
synapse
catalyzed by multifunction oxidase enzymes (MFO) and is important in the mode of
action of CPY. For example, inhibition of MFOs by the synergist piperonyl butoxide
resulted in a decreased toxicity of CPY by up to sixfold in aquatic organisms
(El-Merhibi et al. 2004 ). Chlorpyrifos itself is not a strong inhibitor of AChE, but
when transformed to CPYO, the phosphorus atom in the molecule becomes more
susceptible to nucleophilic attack by the serine hydroxyl in the active site of AChE.
The initial association of CPYO with AChE is reversible ( k 1 , k −1 ; Fig. 4 ) and is
modified by the tertiary structure of the enzyme and the inhibitor. During phos-
phorylation of the serine-OH ( k 2 ; Fig. 4 ), CPYO is hydrolyzed to release the leaving
group TCP (Fig. 4 ), the reaction is no longer reversible, and AChE is inhibited for
as long as it remains phosphorylated. The phosphonic acid moiety is covalently
bound to the serine in AChE but the bond can be cleaved by hydrolysis, unless the
phosphorylated enzyme ages. If the serine-O-P bond is hydrolyzed by water, AChE
is reactivated and normal function returns. If aged via hydrolysis of one of ethyl-
ester bonds (Fig. 4 ), the reactivity of the serine-O-P bond is greatly reduced, AChE
cannot be reactivated, and recovery essentially requires the synthesis of new AChE.
The leaving group, TCP, is several orders of magnitude less toxic than CPY or
CPYO (Giesy et al. 1999 ) and is not of toxicological significance (USEPA 2011a ).
The phosphonic acid released by reactivation of AChE is of low toxicity and is eas-
ily excreted from animals (Timchalk 2010 ). For this reason, the focus of the risk
assessments in this series of papers (Cutler et al. 2014 ; Giddings et al. 2014 ; Moore
et al. 2014 ) is only on CPY and CPYO. It should be noted that CPYO is the acti-
vated form of CPY and its formation in the animal is integral to the mode of action
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