Genetic predisposition to adverse consequences of anti–cholinesterases in ‘atypical’ BCHE carriers

Loewenstein-Lichtenstein, Y; Schwarz, Mikael; Glick, David; Nørgaard‐Pedersen, Bent; Zakut, Haim; Soreq, Hermona

doi:10.1038/nm1095-1082

Cited by 110 publications

(53 citation statements)

References 22 publications

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“…Of the numerous BCHE mutations, we genotyped the D70G substitution yielding the ''atypical'' BChE variant, with enzymatic activity 30% lower than the wild-type enzyme (34). Homozygous carriers of this polymorphism display extreme anxiety after exposure to anti-AChEs (35). Genotypes at all seven positions did not deviate from Hardy-Weinberg equilibrium expectations.…”

Section: Resultsmentioning

confidence: 99%

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Sklan

Lowenthal

Korner

et al. 2004

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

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126

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Anxiety involves complex, incompletely understood interactions of genomic, environmental, and experience-derived factors, and is currently being measured by psychological criteria. Here, we report previously nonperceived interrelationships between expression variations and nucleotide polymorphisms of the chromosome 7q21-22 acetylcholinesterase-paraoxonase 1 (ACHE-PON1) locus with the trait-and state-anxiety measures of 461 healthy subjects from the Health, Risk Factors, Exercise Training, and Genetics Family Study. The AChE protein controls the termination of the stress-enhanced acetylcholine signaling, whereas the PON protein displays peroxidase-like activity, thus protecting blood proteins from oxidative stress damages. Serum AChE and PON enzyme activities were both found to be affected by demographic parameters, and showed inverse, reciprocal associations with anxiety measures. Moreover, the transient scores of state anxiety and the susceptibility score of trait anxiety both appeared to be linked to enzyme activities. This finding supported the notion of corresponding gene expression relationships. Parallel polymorphisms in the ACHE and PON1 genes displayed apparent associations with both trait-and state-anxiety scores. Our findings indicate that a significant source of anxiety feelings involves inherited and acquired parameters of acetylcholine regulation that can be readily quantified, which can help explaining part of the human variance for state and trait anxiety.

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Section: Resultsmentioning

confidence: 99%

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Sklan

Lowenthal

Korner

et al. 2004

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

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126

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“…In human blood, however, BChE, at 50 nM, is 3-fold more abundant than AChE (32). This difference might be physiologically important, because the A␤ fibril-formation process likely involves continuous communication between the brain and the circulation (33) and because BChE interacts with A␤ in the soluble phase.…”

Section: Discussionmentioning

confidence: 99%

Butyrylcholinesterase attenuates amyloid fibril formation in vitro

Diamant¹,

Podoly

Friedler³

et al. 2006

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

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161

101

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In Alzheimer's disease, both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) colocalize with brain fibrils of amyloid-␤ (A␤) peptides, and synaptic AChE-S facilitates fibril formation by association with insoluble A␤ fibrils. Here, we report that human BChE and BSP41, a synthetic peptide derived from the BChE C terminus, inversely associate with the soluble A␤ conformers and delay the onset and decrease the rate of A␤ fibril formation in vitro, at a 1:100 BChE͞A␤ molar ratio and in a dose-dependent manner. The corresponding AChE synthetic peptide (ASP)40 peptide, derived from the homologous C terminus of synaptic human (h)AChE-S, failed to significantly affect A␤ fibril formation, attributing the role of enhancing this process to an AChE domain other than the C terminus. Circular dichroism and molecular modeling confirmed that both ASP40 and BChE synthetic peptide (BSP)41 are amphipathic ␣-helices. However, ASP40 shows symmetric amphipathicity, whereas BSP41 presented an aromatic tryptophan residue in the polar side of the C terminus. That this aromatic residue is causally involved in the attenuating effect of BChE was further supported by mutagenesis experiments in which (W8R) BSP41 showed suppressed capacity to attenuate fibril formation. In Alzheimer's disease, BChE may have thus acquired an inverse role to that of AChE by adopting imperfect amphipathic characteristics of its C terminus.

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“…Organophosphorus poisoning and anaesthesia ................................................................................................................................................................................................................................................ Normal cholinesterase, but not several of its common genetic variants, serves as a scavenger for certain anticholinesterases such as OP compounds. Loewenstein-Lichtenstein et al [118] reported an Israeli soldier homozygous for atypical cholinesterase who suffered severe symptoms following pyridostigmine prophylaxis during the Gulf War. His cholinesterase was far more sensitive than normal cholinesterase to inhibition by anticholinesterases.…”

Section: Biochemistrymentioning

confidence: 99%

Organophosphorus poisoning and anaesthesia

1999

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SummaryOrganophosphorus compounds, used as insecticides and agents of chemical warfare, are a major global cause of health problems. These irreversible inhibitors of cholinesterase produce three wellrecognised clinical entities: the initial cholinergic phase, which is a medical emergency often requiring management in an intensive care unit; the intermediate syndrome, during which prolonged ventilatory care is necessary; and delayed polyneuropathy. In addition, disturbances of body temperature and endocrine function, electrolyte imbalances, immunological dysfunction and disorders of reproduction have been reported in animals and man. Vocal cord paralysis, pancreatitis, cardiac arrhythmias and a wide range of neuropsychiatric disorders are known to follow acute and chronic exposure to organophosphorus compounds. As a result of the inhibition of plasma cholinesterase, there can be increased sensitivity to drugs hydrolysed by this enzyme, e.g. suxamethonium and mivacurium. The inhibition of acetylcholinesterase causes dysfunction at the neuromuscular junction which can produce altered responses to nondepolarising neuromuscular blockers. Anaesthetists may encounter patients exposed to organophosphorus compounds either following acute poisoning, trauma (warfare) or as patients with a wide range of nonspecific disorders presenting for surgery. The traditional use of oximes and atropine in treatment has failed to reduce the morbidity and mortality associated with poisoning. The roles of agents that have reduced the toxicity of organophosphorus compounds in animal experiments are discussed as potential therapeutic agents. There is an urgent need for accurate information on the problems associated with exposure to organophosphorus compounds. This would best be achieved by collaborative research between technologically advanced countries and developing countries, where organophosphorus compounds are a leading cause of ill health.

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Genetic predisposition to adverse consequences of anti–cholinesterases in ‘atypical’ BCHE carriers

Cited by 110 publications

References 22 publications

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Butyrylcholinesterase attenuates amyloid fibril formation in vitro

Organophosphorus poisoning and anaesthesia

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