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

被引:71
作者
Lockridge, Oksana [1 ]
Norgren, Robert B., Jr. [2 ]
Johnson, Rudolph C. [3 ]
Blake, Thomas A. [3 ]
机构
[1] Univ Nebraska Med Ctr, Eppley Inst, 42nd & Emile, Omaha, NE 68198 USA
[2] Univ Nebraska Med Ctr, Genet Cell Biol & Anat, Omaha, NE 68198 USA
[3] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, 4770 Buford Highway,MS F44, Chamblee, GA 30341 USA
基金
美国国家卫生研究院;
关键词
HUMAN-SERUM CHOLINESTERASE; MASS-SPECTROMETRY; KNOCKOUT MOUSE; TOKYO SUBWAY; ERYTHROCYTE ACETYLCHOLINESTERASE; ORGANOPHOSPHATE TOXICITY; RETROSPECTIVE DETECTION; PLASMA CHOLINESTERASE; METHYLPHOSPHONIC ACID; ANTI-CHOLINESTERASES;
D O I
10.1021/acs.chemrestox.6b00228
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1381 / 1392
页数:12
相关论文
共 97 条
[1]   Genetic and immunological analyses of patients with increased serum butyrylcholinesterase activity and its C5 variant form [J].
Akizuki, S ;
Ohnishi, A ;
Kotani, K ;
Sudo, K .
CLINICAL CHEMISTRY AND LABORATORY MEDICINE, 2004, 42 (09) :991-996
[2]   The butyrylcholinesterase K-variant shows similar cellular protein turnover and quaternary interaction to the wild-type enzyme [J].
Altamirano, CV ;
Bartels, CF ;
Lockridge, O .
JOURNAL OF NEUROCHEMISTRY, 2000, 74 (02) :869-877
[3]   Inhibition of acetylcholinesterase and butyrylcholinesterase by chlorpyrifos-oxon [J].
Amitai, G ;
Moorad, D ;
Adani, R ;
Doctor, BP .
BIOCHEMICAL PHARMACOLOGY, 1998, 56 (03) :293-299
[4]   STRUCTURE OF THE GENE FOR HUMAN BUTYRYLCHOLINESTERASE - EVIDENCE FOR A SINGLE COPY [J].
ARPAGAUS, M ;
KOTT, M ;
VATSIS, KP ;
BARTELS, CF ;
LADU, BN ;
LOCKRIDGE, O .
BIOCHEMISTRY, 1990, 29 (01) :124-131
[5]  
BARTELS CF, 1993, AM J HUM GENET, V52, P928
[6]  
BARTELS CF, 1992, AM J HUM GENET, V50, P1086
[7]  
BARTELS CF, 1992, AM J HUM GENET, V50, P1104
[8]   GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors [J].
Benyamin, Beben ;
Middelberg, Rita P. ;
Lind, Penelope A. ;
Valle, Anne M. ;
Gordon, Scott ;
Nyholt, Dale R. ;
Medland, Sarah E. ;
Henders, Anjali K. ;
Heath, Andrew C. ;
Madden, Pamela A. F. ;
Visscher, Peter M. ;
O'Connor, Daniel T. ;
Montgomery, Grant W. ;
Martin, Nicholas G. ;
Whitfield, John B. .
HUMAN MOLECULAR GENETICS, 2011, 20 (22) :4504-4514
[9]   BUTYRYLCHOLINESTERASE IN HUMAN-BRAIN AND ACETYLCHOLINESTERASE IN HUMAN-PLASMA - TRACE ENZYMES MEASURED BY 2-SITE IMMUNOASSAY [J].
BRIMIJOIN, S ;
HAMMOND, P .
JOURNAL OF NEUROCHEMISTRY, 1988, 51 (04) :1227-1231
[10]  
BROCK A, 1990, J CLIN CHEM CLIN BIO, V28, P851