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How azide ion/hydrazoic acid passes through biological membranes : an experimental and computational study
ID Lojevec Hartl, Simona (Author), ID Žakelj, Simon (Author), ID Sollner Dolenc, Marija (Author), ID Smrkolj, Vladimir (Author), ID Mavri, Janez (Author)

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Abstract
Hydrazoic acid (HN$_3$) and its deprotonated form azide ion (N$_3$$^−$) (AHA) are toxic because they inhibit the cytochrome c oxidase complex IV (CoX IV) embedded in the inner mitochondrial membrane that forms part of the enzyme complexes involved in cellular respiration. Critical to its toxicity is the inhibition of CoX IV in the central nervous system and cardiovascular system. Hydrazoic acid is an ionizable species and its affinity for membranes, and the associated permeabilities, depend on the pH values of aqueous media on both sides of the membranes. In this article, we address the permeability of AHA through the biological membrane. In order to understand the affinity of the membrane for the neutral and ionized form of azide, we measured the octanol/water partition coefficients at pH values of 2.0 and 8.0, which are 2.01 and 0.00034, respectively. Using a Parallel Artificial Membrane Permeability Assay (PAMPA) experiment, we measured the effective permeability through the membrane, which is logP$_e$ − 4.97 and − 5.26 for pH values of 7.4 and pH 8.0, respectively. Experimental permeability was used to validate theoretical permeability, which was estimated by numerically solving a Smoluchowski equation for AHA diffusion through the membrane. We demonstrated that the rate of permeation through the cell membrane of 8.46·10$^4$ s$^{-1}$ is much higher than the rate of the chemical step of CoX IV inhibition by azide of 200 s$^{-1}$. The results of this study show that transport through the membrane does not represent the rate-limiting step and therefore does not control the rate of CoX IV inhibition in the mitochondria. However, the observed dynamics of azide poisoning is controlled by circulatory transport that takes place on a time scale of minutes.

Language:English
Keywords:azide ion, hydrazoic acid, octanol/water partition coefficient, effective permeability, PAMPA, diffusion, inhibition, cytochrome c oxidase complex IV
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
MF - Faculty of Medicine
Publication status:Published
Publication version:Version of Record
Year:2023
Number of pages:Str. 229–238
Numbering:Vol. 42, iss. 3
PID:20.500.12556/RUL-147004 This link opens in a new window
UDC:615.4:54:615.9
ISSN on article:1875-8355
DOI:10.1007/s10930-023-10127-3 This link opens in a new window
COBISS.SI-ID:155988995 This link opens in a new window
Publication date in RUL:17.07.2023
Views:1558
Downloads:81
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Record is a part of a journal

Title:The protein journal
Publisher:Springer Nature
ISSN:1875-8355
COBISS.SI-ID:527281689 This link opens in a new window

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.

Secondary language

Language:Slovenian
Keywords:azidni ion, hidrazojska kislina, porazdelitveni koeficient, oktanol/voda, efektivna prepustnost, PAMPA, difuzija, inhibicija, citokrom c oksidazni kompleks IV, toksini, farmacevtska kemija

Projects

Funder:ARRS - Slovenian Research Agency
Project number:P1-0012
Name:Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin

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