Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

Abstract

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.

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

“…Individuals carrying certain variants of BChE with depreciated scavenging ability may be more sensitive to OPs than the majority of the population (Lockridge et al . ). Albumin reacts slowly with OPs but is so much abundant in plasma and lymph (0.6 mM) that it has a moderate detoxication role (Sogorb and Vilanova ).…”

Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold

“…By degradation of acetylcholine, AChE fulfills its physiological role allowing maintence of optimal neurotransmission. This role is shared by AChE with the related enzyme BChE that does not possess a known physiological substrate, but does have a role in the bioconversion of several xenobiotics, in the metabolism of lipoproteins and, in cases when the activity of AChE is low or inhibited, serves as AChE backup enzyme [ 1 ]. BChE and AChE share almost the same backbone structure with a more than 50% identical amino acid sequence and an active site located in a 20 Å deep gorge [ 2 – 4 ].…”

K-variant BCHE and pesticide exposure: Gene-environment interactions in a case–control study of Parkinson’s disease in Egypt

“…BChE is 10-fold more common in the body than AChE, yet it does not have unique physiological functions that cannot be compensated by other enzymes. It does, however, play an important role as a bioscavenger protecting against organophosphate and carbamate toxicity 24 . These pesticides prevent degradation of ACh thus causing its accumulation and overstimulation of nerves and muscles with resulting toxic effects 25 .…”

“…Blood-cell-derived genomic DNA (80–100 ng/µL) was genotyped with the EP1 platform on 96.96 Dynamic Array and read by Fluidigm EP1 Genetic Analysis Scanner (Fluidigm Corporation, San Francisco, CA). Twenty-four Candidate SNPs were chosen in genes related to pesticide detoxification [ CYP1B1 (rs1056836) 36 , CYP2B6 (rs3745274) 37 , CYP2C9 (rs1799853, rs1057910) 32 , CYP2C18 (rs2296680) 38 , CYP2E1 (rs2070676) 39 , PON1 (rs662, rs854560, rs854572) 40 , GSTO1 (rs11191972, rs4925) 41 , GSTO2 (rs2297235, rs156697) 41 , NAT1 (rs5030839, rs4987076) 42 , 43 , NAT2 (rs15561) 43 , NQO1 (rs1800566) 9 , COMT (rs4680) 36 , BCHE (rs1803274, rs1799807, rs1126680) 24 , 29 , 44 , PLA2G6 (CM1211192) 45 ] and pesticide transport [ SLC6A3 (rs27072, rs2550956) 14 , 46 ]. Assays include tagged, allele-specific PCR forward-primers and a common reverse primer.…”