Inherited and acquired interactions between ACHE and PON1 polymorphisms modulate plasma acetylcholinesterase and paraoxonase activities

Abstract

The 5.5 Mb chromosome 7q21-22 ACHE/PON1 locus harbours the ACHE gene encoding the acetylcholine hydrolyzing, organophosphate (OP)-inhibitable acetylcholinesterase protein and the paraoxonase gene PON1, yielding the OP-hydrolyzing PON1 enzyme which also displays arylesterase activity. In search of inherited and acquired ACHE-PON1 interactions we genotyped seven polymorphic sites and determined the hydrolytic activities of the corresponding plasma enzymes and of the AChE-homologous butyrylcholinesetrase (BChE) in 157 healthy Israelis. AChE, arylesterase, BChE and paraoxonase activities in plasma displayed 5.4-, 6.5-, 7.2-and 15.5-fold variability, respectively, with genotype-specific differences between carriers of distinct compound polymorphisms. AChE, BChE and arylesterase but not paraoxonase activity increased with age, depending on leucine at PON1 position 55. In contrast, carriers of PON1 M55 displayed decreased arylesterase activity independent of the ) 108 promoter polymorphism. Predicted structural consequences of the PON1 L55M substitution demonstrated spatial shifts in adjacent residues. Molecular modelling showed substrate interactions with the enzyme variants, explaining the changes in substrate specificity induced by the Q192R substitution. Intriguingly, PON1, but not BChE or arylesterase, activities displayed inverse association with AChE activity. Our findings demonstrate that polymorphism(s) in the adjacent PON1 and ACHE genes affect each other's expression, predicting for carriers of biochemically debilitating ACHE/PON1 polymorphisms adverse genome-environment interactions.

Original article Paraoxonase 1 (PON1) gene -108C>T and p.Q192R polymorphisms and arylesterase activity of the enzyme in patients with dementia

“…The carriers of R allele were found to be better responders [27]. This influence of the polymorphism could result from the interaction between PON1 and cholinesterase [4,21].…”

“…Several authors reported that when PON1 activity was measured using arylester as a substrate, no differences depending on Q192R polymorphism were observed. It was often admitted that paraoxon was a discriminating substrate and phenylacetate was a non-discriminating one [4,9,20,23].…”

Decline in Serum Cholinesterase Activities Predicts 2-Year Major Adverse Cardiac Events

“…To compare the effects of AChE, BChE and cholinergic status changes on cardiovascular risk, we used ATCh as a substrate with or without tetraisopropyl pyrophosphoramide (iso-OMPA, a specific BChE inhibitor), thus identifying AChE alone, mimicking the total impact of ACh hydrolysis and enabling a calculation of BChE contribution. This method has been reliably used in several recent studies (14,(19)(20)(21)(22)(23).…”

Serum Paraoxonase-1 (PON-1) Genotype and Exposure to Organophosphorous Insectides—Is There a High-Risk Population?

“…Interestingly, the genes which code for PON-1 and AchE, the major target for OP compounds, are located in close proximity on chromosome 7q21-22. This suggests that polymorphisms in these adjacent genes can impact each other's expression, which can impact sensitivity to agents that inhibit cholinesterase enzymes [11].…”

“…This evidence also suggests that not only is PON-1 protective against OP toxicity, but that exogenous PON-1 may have a potential therapeutic role in protecting individuals exposed to OP compounds (agricultural workers exposed to pesticides or soldiers at risk for exposure to a nerve agent). Thus far, only one study exists which incorporated objective data into its methodology, (cholinesterase testing results), which were determined to be poor markers for OP toxicity [11]. In addition to PON-1 genotype, direct measurement of PON-1 activity and correlation with signs, symptoms, and objective data in real patients may also help to increase understanding of the importance of PON-1 in OP metabolism and toxicity.…”