Paraoxon potency

An example of biotoxification is the formation of paraoxon from the insecticide parathion via sulfoxidation. The simple substitution of an oxygen atom for a sulfur atom in the molecule results in a cholinesterase inhibitor with several times more potency. Similarly, the toxic action of methanol in producing blindness is the result of its metabolism to formaldehyde. Examples of bioactivation and biotoxification reactions are shown in Figure 3.2. 

Jun, D., Musilova, L., Lazenska, H., Kuca, K., Kassa, J., Bajgar, J. (2007). Potency of several oximes to reactivate human acetylcholinesterase and hutyrylcholinesterase inWhited by paraoxon and methyl-paraoxon in vitro. The IXth International Meeting on Cholinesterases. Suzhou, CWna, May 6-10, 2007. Program Book, p. 140. 

Chlorpyrifos, disfulfoion. EPN. fenthion. parathion-ethyl, and parathion-methyl at I jM inhibit nAChRs more potently than I rajWAChE 15 other OP compounds tested (e.g., malaoxon, malathion. Icptophos. and paraoxon-ethyl) are not as potent potency order ford OP compounds tested further against I ACh is disfulfoion (7 (ji.Vf) > parathion-ethyl > parathion methyl > fenthion (75 juA/)- Binding studies indicate that OP rapidly and reversibly bind.s to the receptor followed by stabilisation of the blocked state or receptor dcsensiiizatinn. OP compounds appear to interact directly with 0(4 2 nAChRs. 

Jeong, H.C., Kang, N.S., Park, N.J., et ak, 2009. Reactivation potency of fluori-nated pyridinium oximes for acetylcholinesterases inhibited by paraoxon organophosphorus agent. Bioorg. Med. Chem. Lett. 19, 1214-1217. 

Oh, K. A., Park, N.J., Park, N.S., et al., 2008. Determination of reactivation potency for DFP- and paraoxon-inhibited acetylcholinesterases by pyridinium oximes. Chem. Biol. Interact. 175, 365-367. 

Inhibition profiles were determined for phosphorothioate OP insecticides such as parathion, malathion, and diazinon (Figure 3). Because these compounds were only weakly inhibitory, the measured concentration range extended from 0.1 nM to 100 pM. The relative order of potency was malathion > diazinon > parathion. The commercially available oxidative transformation products of parathion and malathion (i.e., paraoxon and malaoxon) as well as dichlorvos, were also measured using this assay (Figure 4). The oxidative transformation products were significantly more potent AChE inhibitors than the parent compounds and showed inhibitory profiles comparable to dichlorvos. The cholinesterase inhibition assay yielded similar IC50 values for each of these compounds. Indeed, these compounds are typically reported to have inhibition constants within an order of magnitude of each other (16, 17). 

IC50 Values Because of its stability, strong inhibitory effect and commercial availability, paraoxon has often been used as a reference compound for cholinesterase inhibition (7). Asa result of the widespread use of paraoxon as a reference inhibitor, we elected to compare the relative potency of compounds assayed to this inhibitor in the form of paraoxon equivalence. IC50 values and % inhibition relative to paraoxon (paraoxon equivalence) were determined for a wide range of cholinesterase inhibitors (Table III). The extent to which the data fit a four parameter curve fit or log-logit fit are also included as correlation coefficients. The compounds are placed in ascending order of calculated IC50 values. 

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