Sensitivity of butyrylcholinesterase knockout mice to (--)-huperzine A and donepezil suggests humans with butyrylcholinesterase deficiency may not tolerate these Alzheimer's disease drugs and indicates butyrylcholinesterase function in neurotransmission.
Butyrylcholinesterase (EC 3.1.1.8 BChE) is present in all human and mouse tissues, and is more abundant than acetylcholinesterase (EC 3.1.1.7 AChE) in all tissues except brain. People who have no BChE activity due to a genetic variation are healthy. This has led to the hypothesis that BChE has no physiological function. We tested this hypothesis by challenging BChE and AChE knockout mice, as well as wild-type mice, with the AChE specific inhibitors, (--)-huperzine A and donepezil, and with serine hydrolase inhibitors, echothiophate and chlorpyrifos oxon. (--)-Huperzine A and donepezil caused mortality and significant toxicity in the BChE-/- animals. The BChE heterozygote (BCHE+/-) mice with approximately one-half the BChE activity of the BChE wild type (BChE+/+) exhibited intermediate toxic symptoms, and survived a longer period. The BChE+/+ animals displayed comparatively minor toxic symptoms and recovered by 24h post-dosing. Plasma AChE activity was inhibited to the same extent in BChE-/-, +/-, and +/+ mice, whereas BChE activity was not inhibited. This indicated that the protective effect of BChE was not due to scavenging (--)-huperzine A. AChE-/- mice were unaffected by (--)-huperzine A and donepezil, demonstrating the specificity of these inhibitors for AChE. AChE-/- mice treated with chlorpyrifos oxon lost all BChE activity, had severe cholinergic symptoms and died of convulsions. This showed that BChE activity was essential for survival of AChE-/- mice. In conclusion, we propose that the protective effect of BChE is explained by hydrolysis of excess acetylcholine in physiologically relevant regions such as diaphragm, cardiac muscle, and brain. Thus, BChE has a function in neurotransmission. People with BChE deficiency are expected to be intolerant of standard doses of the anti-Alzheimer's drugs, (--)-huperzine A and donepezil.
Duysen
Ellen G
EG
Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA. eduysen@unmc.edu
Li
Bin
B
Darvesh
Sultan
S
Lockridge
Oksana
O
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D002091:Butyrylcholinesterase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004390:Chlorpyrifos / Q000031:analogs & derivatives / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000517:prevention & control; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects*
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D012717:Sesquiterpenes; C050426:huperzine A; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D000077265:Donepezil; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D004390:Chlorpyrifos; D000109:Acetylcholine