Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite phorate oxon (PHO)

Abstract

Phorate is a highly toxic agricultural pesticide currently in use throughout the world. Like many other organophosphorus (OP) pesticides, the primary mechanism of the acute toxicity of phorate is acetylcholinesterase (AChE) inhibition mediated by its bioactivated oxon metabolite. AChE reactivation is a critical aspect in the treatment of acute OP intoxication. Unfortunately, very little is currently known about the capacity of various oximes to rescue phorate oxon (PHO)-inhibited AChE. To help fill this knowledge gap, we evaluated the kinetics of inhibition, reactivation, and aging of PHO using recombinant AChE derived from three species (rat, guinea pig and human) commonly utilized to study the toxicity of OP compounds and five oximes that are currently fielded (or have been deemed extremely promising) as anti-OP therapies by various nations around the globe: 2-PAM Cl, HI-6 DMS, obidoxime Cl2, MMB4-DMS, and HLö7 DMS. The inhibition rate constants (k i) for PHO were calculated for AChE derived from each species and found to be low (i.e., 4.8 × 103 to 1.4 × 104 M−1 min−1) compared to many other OPs. Obidoxime Cl2 was the most effective reactivator tested. The aging rate of PHO-inhibited AChE was very slow (limited aging was observed out to 48 hours) for all three species. Conclusions: (1) Obidoxime Cl2 was the most effective reactivator tested. (2) 2-PAM Cl, showed limited effectiveness in reactivating PHO-inhibited AChE, suggesting that it may have limited usefulness in the clinical management of acute PHO intoxication. (3) The therapeutic window for oxime administration following exposure to phorate (or PHO) is not limited by aging.

A Rare Case of Suicide by Ingestion of Phorate: A Case Report and a Review of the Literature

“…Nevertheless, organophosphorus pesticide (OP) disrupts many other neurotransmitters, and some of these are entailed in mood regulation, such as serotonin. This could clarify the connection between pesticide exposure and mood disorders seen in earlier studies [ 39 , 40 ].…”

“…Recent studies have highlighted that long-term low/moderate exposure to OP could be correlated with impaired neurobehavioral function or other neurological effects [ 32 , 33 ], while the studies have reported higher suicide rates among farmers who used it than in the general population [ 34 , 35 ]. Other investigations on the chronic toxicity of OP have shown kidney damage in animal models mediated by several mechanisms such as damage to the cell membrane and proteins through oxidative stress induced by the generation of free oxygen radicals, functional disturbances related to plasma membrane injury, cellular DNA damage, and activation of apoptosis-related p53 [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. In the present study, we report a case of suicide carried out through the high ingestion of phorate of an agricultural worker exposed to phorate, at low doses, for several years.…”

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [18F]‐VXS

“…Therefore, [ 18 F]‐VXS was selected as a tracer to develop a quantitative PET imaging platform to measure available/functional AChE in live tissues following OP exposure and after intervention with oximes. POX was chosen as the OP challenge agent since it is a potent anticholinesterase inhibitor, affords a predictable toxicological profile, and the diethylphosphoryl–AChE adduct formed by POX (or related diethoxy phosphorylating agents, such as phorate 44 ) undergoes reactivation by oximes and does not age in the hours following AChE inhibition 45 …”

Inhibition of Acetylcholinesterases by Stereoisomeric Organophosphorus Compounds Containing Both Thioester and p-Nitrophenyl Leaving Groups

“…Alternatively, dealkylation of a phosphorus ester can occur via aging (loss of R; k 4 ), thereby sustaining the AChE blockade , (Figure ). Aged OP-AChE adducts are concerning because they are recalcitrant to reactivation even with oxime antidotes. − …”