Reactivation kinetics of 31 structurally different bispyridinium oximes with organophosphate-inhibited human butyrylcholinesterase

Abstract

Organophosphorus compounds (OP) are bound to human butyrylcholinesterase (BChE) and endogenous or exogenous BChE may act as a stoichiometric scavenger. Adequate amounts of BChE are required to minimize toxic OP effects. Simultaneous administration of BChE and oximes may transfer the enzyme into a pseudo-catalytic scavenger. The present study was initiated to determine the reactivation kinetics of 31 structurally different bispyridinium oximes with paraoxon-, tabun- and cyclosarin-inhibited human BChE. Human plasma was incubated with OP and the reactivation of inhibited BChE was tested with multiple oxime concentrations followed by nonlinear regression analysis for the determination of reactivity, affinity and overall reactivation constants. The generated data indicate that the tested oximes have a low-to-negligible reactivating potency with paraoxon- and tabun-inhibited human BChE. Several oximes showed a moderate-to-high potency with cyclosarin-inhibited BChE. Thus, the present study indicates that bispyridinium oximes are obviously not suitable to serve as reactivators of human BChE inhibited by different OP and it is doubtful whether further modifications of the bispyridinium template will lead to more potent reactivators. In the end, novel structures of oxime and non-oxime reactivators are urgently needed for the development of human BChE into an effective pseudo-catalytic scavenger.

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

“…Unfortunately, known pyridinium oxime reactivators are too slow at reactivating huBChE (Horn et al . ), and prompted the search for specific BChE efficient reactivators (Kovarik et al . ).…”

Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment

“… References: a=[ 154 ] b=[ 155 ] c=[ 156 ] d=[ 157 ] e=[ 158 ] f=[ 159 ] g=[ 160 ] h=[ 161 ] i=[ 162 ] j=[ 163 ] k=[ 164 ] l=[ 165 ] m=[ 166 ] n=[ 167 ] o=[ 168 ] p=[ 169 ] q=[ 170 ] r=[ 171 ] s=[ 172 ] t=[ 173 ] u=[ 147 ] v=[ 174 ], w=[ 175 ] x=[ 176 ]. …”

A case report of cholinesterase inhibitor poisoning: cholinesterase activities and analytical methods for diagnosis and clinical decision making

“…Fig. 3a, b) (Worek et al 2012;Horn et al 2015). Relying only on BChE data, one could get the misleading impression that obidoxime administration does not result in reactivation and, therefore, not lead to the improvement of synaptic AChE activity and, a better neuromuscular transmission consequently (Thiermann et al 2005).…”

“…A possible explanation might be the latteridentified-OP parathion and its active biotransformation product, paraoxon, respectively. The reactivation of paraoxon-inhibited BChE with obidoxime is characterized by a low-reactivity constant (k r 0.07 min −1 ) and a low-affinity constant (K D 317 µM) (Horn et al 2015). On the basis of these kinetic parameters and the in vivo obidoxime concentration (10 µM), a reactivation half-time of paraoxon-inhibited BChE of > 300 min was calculated, being much too low for effective catalytic scavenging.…”