Naslov
Can the BCHE polymorphism affect the inhibition potency of carbamylating and reversible inhibitors from everyday life?

Autori
Bosak, Anita ; Kovarik, Zrinka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstract of 10th Joint Meeting on Medicinal Chemistry, Dubrovnik (Srebreno) / Basarić, Nikola ; Namjesnik, Danijel ; Perković, Ivana ; Stepanić, Višnja - Zagreb : Hrvatsko kemijsko društvo, 2017

ISBN
978-953-55232-8-4

Skup
10th Joint Meeting on Medicinal Chemistry

Mjesto i datum
Srebreno, Hrvatska; Dubrovnik, Hrvatska, 25.06.2017. - 28.06.2017

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
butyrylcholinesterase, carbamates, flaovnoids, bronchodilators

Sažetak
Butyrylcholinesterase (BChE) serves as a co-regulator of cholinergic neurotransmission because it can efficiently hydrolyse the neurotransmitter acetylcholine, which is primarily the role of acetylcholinesterase (AChE). Recently, BChE and its impact on the development and progression of Alzheimer's disease have become increasingly important and the inhibition of BChE appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels.[1] However, one should keep in mind that today, more than 56 mutations of the human BCHE gene have been identified and different catalytic properties or lower enzyme levels than of usual BChE have been confirmed for several BChE variants. Ample evidence demonstrates that individuals with the unusual BChE polymorphism respond differently to anti-AChEs ; e.g. individuals homozygous for atypical BChE (carries the BCHE mutation D70G) can experience prolonged apnea if the muscle relaxant succinylcholine and mivacurium are administered and individuals with silent BChE are more susceptible to organophosphorus compounds than that of usual BChE.[2] This study evaluated the inhibition of atypical and fluoride-resistant BChE (carries BCHE mutations T243M or G390V) variants with the aim of relating the BChE polymorphism by two groups of compounds that differ in the mode of binding to BChE. One group were ligands such as certain -adrenergic agonists and flavonoids that bind to the enzyme with noncovalent interactions. The second group contained inhibitors like carbamate derivatives of bronchodilatators terbutaline (bambuterol), metaproterenol and isoproterenol, which covalently bind to the catalytic serine in the active site of the enzyme. Our results have shown that all of the tested compounds reduced human BChE activity and therefore can affect their use as drugs or food supplements. All three of the tested carbamates had an about 50 and 100 times higher inhibition potency for usual BChE than for atypical and fluoride-resistant BChE, respectively.[3] Similarly, the tested 2-agonists showed the highest inhibition potency towards usual BChE, while atypical and fluoride-resistant variants were up to 26 and 2.8 times (depending on structure), respectively, less inhibited than usual BChE. However, in the case of flavonoids, we showed that no significant change in their inhibition potency exists in view of the BCHE polymorphism.[4] Therefore, our results emphasize that in the case of carbamates and 2-agonists, individuals - carriers of atypical BChE variants will be less affected compared to the usual variant. This is especially important for drugs for which BChE is a key enzyme in the metabolism. Acknowledgement: Supported by HrZZ4307 [1] A. Tasker, E.K. Perry, C.G. Ballard, Expert Rev. Neurother 2005, 5, 101–106. [2] O. Lockridge, P. Masson, Neurotoxicology 2000, 21, 113-126. [3] A. Bosak, I. Gazić Smilović, G. Šinko, V. Vinković, Z. Kovarik, J. Med. Chem. 2012, 55, 6716-6723M. [4]. Katalinić, A. Bosak, Z. Kovarik, Food Technol. Biotechnol. 2014, 52, 64-67.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Javno zdravstvo i zdravstvena zaštita, Farmacija

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