Organophosphates are insecticides which result in acute adverse signs when exposed at toxic doses by animals and lead to death if left untreated. The current treatment for organophosphate toxicity includes atropine and the federally approved oxime 2-PAM. However, 2-PAM is not very effective at crossing the blood brain barrier which results in prolonged inactivation of acetylcholinesterase, which is the primary target of organophosphates, in the brain even after administration. The novel oximes, Oxime 15 and Oxime 20, are able to cross the blood brain barrier and reactivate the inhibited acetylcholinesterase. In this experiment with six animal species frequently used in toxicity studies, they were proven to be just as effective and sometimes better than 2-PAM at reactivating acetylcholinesterase or butyrylcholinesterase inhibited by paraoxon, chlorpyrifos-oxon, phorate-oxon, or dicrotophos. The detoxication enzymes butyrylcholinesterase, carboxylesterase, and paraoxonase were also studied as potential influences of the toxicity of the organophosphates in these different species.

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Paraoxonase-1 (PON1) is a high density lipoprotein (HDL)-associated enzyme displaying esterase and lactonase activity. PON1 hydrolyzes the oxons of several organophosphorous insecticides (e.g. paraoxon, diazoxon and chlorpyrifos-oxon) and metabolizes lipid peroxides of low density lipoproteins (LDL) and HDL. As such, PON1 plays a relevant role in determining susceptibility of organophosphate toxicity and cardiovascular disease. The objective of this study was to determine associations of PON1 status (i.e. genotype and activity levels) with atherosclerosis (ATH) in individuals from the Southeastern United States. An additional objective was to determine whether PON1 genotype and/or PON1 activity levels influence the capacity of PON1 to metabolize chlorpyrifos-oxon (CPO) at a relatively low concentration. Data indicated increasing PON1 activity assessed by hydrolysis of phenyl acetate is associated with decreased odds of ATH. Furthermore, neither PON1 genotype nor PON1 activity levels influence capacity of PON1 to metabolize CPO at a relatively low concentration.

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are inhibited by nerve agents such as sarin and tabun. In general, the inhibited enzymes are reactivated by bisquaternary ammonium compounds (oximes). The binding free energies of the oximes; 2-PAM, MMB-4, HI-6, and obidoxime bound to human AChE (hAChE) and human BChE (hBChE) inhibited by sarin and tabun and also to the uninhibited enzymes were calculated using various computational methods. Using thermodynamic integration, the binding free energies of all the inhibited and uninhibited systems of MMB-4 and obidoxime were evaluated. The standard binding free energies (dA) were more negative than the experimental values due to limitations of the ff99 forcefield. The RMS error of dA for the inhibited systems of MMB-4 was 2.1 kcal/mol, and for obidoxime systems it was 4.8 kcal/mol with respect to the experimental free energies. The binding enthalpies calculated using MM-GBSA and MM-PBSA methods for 2-PAM, MMB-4, HI-6, and obidoxime systems were negative, except for hBChE-sarin-MMB-4 and hBChE-sarin-obidoxime. For all the systems the TdS values calculated using normal mode analysis were equal to or lower in magnitude than their corresponding binding enthalpies. As a result, the estimated free energies were positive for most of the systems. Clearly, the present algorithms cannot effectively estimate the binding entropies for a protein-ligand system. Met81 has commonly shown favorable interactions, and lysine or arginine exhibited unfavorable interactions with the reactivator in all the systems. Second, the interactions between chloropyrifos-oxon (Cpo) and experimentally tested neutral and monopyridinium oximes bound to the Q192 or R192 polymorphs of human paraoxonase1 (hPON1) were studied. The equilibrated Q192 and R192 hPON1 were structurally different than the crystal structure of recombinant PON1. The neutral oximes have shown more favorable interactions with Cpo in Q192 hPON1 + Cpo system compared to R192 hPON1 + Cpo. Whereas the monopyridinium oximes interacted more affectively with Cpo in R192 hPON1 than Q192 hPON1. The relative deprotonation energy of the monopyridinium oxime was lower than the neutral oxime. Hence, the monopyridinium oxime can hydrolyze an organophosphate at a higher rate than a neutral oxime.

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