The Butyrylcholinesterase Knockout Mouse as a Model for Human Butyrylcholinesterase Deficiency

Li, Bin; Duysen, Ellen G.; Carlson, Michaela; Lockridge, Oksana

doi:10.1124/jpet.107.133330

Cited by 102 publications

(71 citation statements)

References 37 publications

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“…It is important to note that mice (and other rodents but much less so for guinea pigs) have a high plasma concentration of carboxylesterase, allowing efficient scavenging of POX (56)(57)(58), and can provide an explanation for their resistance to poisoning by POX (and some other OPs) and to the better than 1∶1 stoichiometry observed here (Fig. 5).…”

Section: Discussionmentioning

confidence: 75%

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

Geyer

Kannan

Garnaud

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic acetylcholinesterase) or nonexisting (synaptic acetylcholinesterase). Here we identify a unique form of recombinant human butyrylcholinesterase that mimics the native enzyme assembly into tetramers; this form provides extended effective pharmacokinetics that is significantly enhanced by polyethylene glycol conjugation. We further demonstrate that this enzyme (but not a G117H/E197Q organophosphorus acid anhydride hydrolase catalytic variant) can prevent morbidity and mortality associated with organophosphorous nerve agent and pesticide exposure of animal subjects of two model species.countermeasures | nonconventional warfare agents | organophosphorous pesticides | protein engineering | transgenic plants B utyrylcholinesterase (BChE) is the major cholinesterase (ChE) in the serum of humans (1, 2). Although the closely related enzyme acetylcholinesterase (AChE) is well described as the primary synaptic regulator of cholinergic transmission, a definitive physiological role for BChE has not yet been demonstrated (3). BChE is catalytically promiscuous and hydrolyzes not only acetylcholine (ACh), but also longer-chain choline esters (e.g., butyrylcholine, its preferred substrate, and succinylcholine) and a variety of non-choline esters, such as acetylsalicylic acid (aspirin) and cocaine (4, 5). Moreover, BChE binds most environmentally occurring ChE inhibitors as well as man-made organophosphorous (OP) pesticides and nerve agents (NAs) (6, 7-10).The systemic biodistribution and affinity for ChE inhibitors allow endogenous BChE to provide broad-spectrum protection against various toxicants by their sequestration before they reach cholinergic synapses. However, under realistic high-dose exposure scenarios, BChE serum levels are too low to afford adequate protection, resulting in persistent cholinergic excitation due to irreversible inhibition of AChE and subsequent accumulation of ACh. Sublethal manifestations of this state include unregulated exocrine secretion and gastrointestinal hypermotility. Death usually results from unregulated stimulation at neuromuscular junction leading to hemodynamic instability and tetanic contraction of the respiratory muscles (11,12).Current OP poisoning therapy consists of atropine for muscarinic ACh receptor blockade and diazepam for symptomatic management of convulsions (12). Additionally, oxime therapy with 2-pralidoxime (2-PAM) can effectively reactivate some but not all OP-AChE adducts (13)(14)(15). This standard therapeutic approach can reduce mortality, but insufficiently prevents the incapacitation associated with OP toxicity (12, 16).Prophylaxis by administration of exogenous ChEs has proven successful in reducing OP-associated morbidity and mortality, but requires the availability of rel...

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Section: Discussionmentioning

confidence: 75%

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

Geyer

Kannan

Garnaud

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…BuChE deficient individuals are generally healthy with no manifest signs of disease 4 . The case is similar for mice with a damaged BuChE gene 5,6 . BuChE deficient individuals have increased sensitivity to muscle relaxants such as succinylcholine, resulting in lasting breath insufficiency 7 .…”

Section: Butyrylcholinesterasementioning

confidence: 89%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

325

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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“…The evidence of BChE was expected to be found once butyrylcholinesterase knockout animals were prepared. However, physical examination of BChE(+/+) and BChE(-/-) did not prove any signifi cant alterations in basal body functions (17). People with BChE defi ciency, i.e.…”

Section: Role Of Butyrylcholinesterase In the Bodymentioning

confidence: 83%

Butyrylcholinesterase as a biochemical marker

Pohanka¹

2013

BLL

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Butyrylcholinesterase (BChE) is an enzyme expressed in multiple organs and abundant in plasma. BChE can fl uctuate in course of several reasons while both hypercholiensterasemia and hypocholinesterasemia are known. Considering evidence of BChE activity alterations, hepatocellular carcinoma, chronic liver diseases and poisoning with carbamates or organophosphates can be diagnosed by activity assay. BChE is responsible for detoxifi cation reactions, and the compounds such as cocaine, succinylcholine, and acetylsalicylic acid are degraded in the body. The detoxifi cation can be slowed in patients carrying the K variant of the enzyme. Summarization of literature, discussion on the meaning of BChE in the body, and the principles of BChE assay in samples are described in the review (Tab. 2, Fig. 8, Ref. 86). Text in PDF www.elis.sk.

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The Butyrylcholinesterase Knockout Mouse as a Model for Human Butyrylcholinesterase Deficiency

Cited by 102 publications

References 37 publications

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

Cholinesterases, a Target of Pharmacology and Toxicology

Butyrylcholinesterase as a biochemical marker

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