. "G: Inhibition of Cholinesterases and an Evaluation of the Methods Used to Measure Cholinesterase Activity." Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents. Washington, DC: The National Academies Press, 1999.
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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents
(Aldridge and Reiner 1972). The A esterases have a serine catalytic site. The tertiary structure and amino acid sequences of several AChEs and BuChEs have been established (Taylor 1994). AChEs regulate excitation at cholinergic synapses, destroying the neurotransmitter ACh. AChE is one of the most active enzymes known, cycling within a few milliseconds (Taylor 1996). AChEs are found at synapses and neuromuscular junctions, and in central-nervous-system (CNS) neuron cell bodies, axons, muscles, red blood cells (RBCs), and platelets of ovine and rodent species (Silver 1974; Traina and Serpietri 1984; Hoffmann et al. 1989).
There is AChE-like activity in the plasma of some birds and mammals (Traina and Serpietri 1984; Smucker and Wilson 1990). Plasma ChE of rodents, such as the laboratory rat, is high in both AChE and BuChE activities (Traina and Serpietri 1984). AChE activity in human blood is found mainly in RBCs (Silver 1974). AChE activity also occurs in the serum of developing mammals and birds, decreasing to adult levels after birth (Smucker and Wilson 1990). Together with AChEs, BuChEs are also found at synapses, motor end plates, and muscle fibers. BuChE activity in blood is restricted to serum (Silver 1974)
Substrate preferences for AChEs and BuChEs vary with the species. Both mammal and bird AChEs rapidly hydrolyze ACh and its thiocholine analog acetylthiocholine (AcTh) (Silver 1974). Plasma-BuChE activity in the rat is reported to favor propionyl rather than butyryl substrates (Augustinsson 1948; Hoffmann et al. 1989). AChEs and BuChEs respond differently to increasing substrate concentration. AChEs are inhibited by excess substrate above 1–2 millimolars (mM) (Wilson et al. 1997; Silver 1974). BuChEs are less sensitive. BuChEs are preferentially inhibited by the selective inhibitor iso-OMPA and quinidine, and AChEs by the bisquaternary compound BW284c51.
The action of AChE on ACh is a multistep process, represented below by the formation of a reversible enzyme-substrate complex (EAX), acetylation of the catalytic site (EA), and hydrolysis of the enzyme-substrate complex yielding acetic acid, choline, and the regenerated enzyme (E + A). A similar reaction scheme is applicable to BuChEs.