Interactions of paraoxonase-1 with pharmacologically relevant carbamates

Bosak, Anita (author), Bavec, Aljoša (author), Konte, Tilen (author), Šinko, Goran (author), Kovarik, Zrinka (author), Goličnik, Marko (author)

Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates influence the activity of recombinant PON1 (rePON1). Carbamates were selected having a variety of applications: bambuterol and physostigmine are drugs, carbofuran is used as a pesticide, while Ro 02-0683 is diagnostic reagent. All the selected carbamates reduced the arylesterase activity of rePON1 towards the substrate S-phenyl thioacetate (PTA). Inhibition dissociation constants (K$_i$), evaluated by both discontinuous and continuous inhibition measurements (progress curves), were similar and in the mM range. The rePON1 displayed almost the same values of K$_i$ constants for Ro 02-0683 and physostigmine while, for carbofuran and bambuterol, the values were approximately ten times lower and two times higher, respectively. The affinity of rePON1 towards the tested carbamates was about 3-40 times lower than that of PTA. Molecular modelling of rePON1-carbamate complexes suggested non-covalent interactions with residues of the rePON1 active site that could lead to competitive inhibition of its arylesterase activity. In conclusion, carbamates can reduce the level of PON1 activity, which should be kept in mind, especially in medical conditions characterized by reduced PON1 levels.

• Language: English
• Keywords: paraoxonase-1, arylesterase activity, reversible inhibition, phenyl acetate, S-phenyl thioacetate, p-nitrophenyl acetate, carbamates
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 15 str.
• Numbering: Vol. 25, iss. 1, art. 211
• PID: 20.500.12556/RUL-133284
• UDC: 577
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules25010211
• COBISS.SI-ID: 34631385
• Publication date in RUL: 19.11.2021

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 04.01.2020

Secondary language

• Language: Slovenian
• Keywords: paraoksonaza-1, arilesterazna aktivnost, reverzibilna inhibicija