
<div xmlns="http://www.w3.org/1999/xhtml">
<p>Dear Editor,</p>
<p>In Volume 70 (pages 134–139) of <italic>Arhiv za higijenu rada i toksikologiju</italic> – <italic>Archives of Industrial Hygiene and Toxicology</italic>, I published a paper entitled “The relationship between antioxidant activity, first electrochemical oxidation potential, and spin population of flavonoid radicals” (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>). The paper detected a problem with hesperetin, a flavonoid (flavanone) with 4′-methoxy and 3′-hydroxyl groups on the B ring. That problem was later resolved in a paper published in the <italic>Journal of Molecular Liquids</italic> (2021;335:116223) on a set of 29 flavonoids (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_002">2</a>), which I believe is worth reporting as a follow-up to my aforementioned article published in the <italic>Archives</italic>.</p>
<p>More precisely, in my paper (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>), I detected hesperetin as an outlier in regression models for the estimation of both oxidation potential (<italic>E</italic><sub>p1</sub>) and antioxidant activities (AA), on a set of 14 flavonoids. The models [Models 2 and 7, Figures 2 and 3 in (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>)] were based on the sum of atomic orbital spin populations over the carbon atoms in the skeleton of a flavonoid radical, 
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<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
, calculated using semiepirical PM6 method. Later, in our paper on <italic>E</italic><sub>p1</sub> models for 29 flavonoids (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_002">2</a>), we succeeded in resolving a problem with hesperetin and its glycosides, hesperidin and neohesperidin, thanks to studies on the electron donation potential of the <italic>ortho</italic>-methoxy group in quinones (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_003">3</a>, <a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_004">4</a>). When we fixed the methoxy group, placing it outside of the plane (orthogonally to the B ring) during optimization, the calculated 
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<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>c</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
 for hesperetin, hesperidin, and neohesperidin fit into the model perfectly, <a ref-type="fig" href="#j_aiht-2024-75-3823_fig_001">Figure 1</a> in (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_002">2</a>) [see more details about approaching certain flavonoids, like flavanones, isoflavones, and flavonoids with <italic>O</italic>-glycosyl, galloyl and methoxy substituents, as well as a new models that we introduced in (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_002">2</a>, <a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_005">5</a>, <a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_006">6</a>)].</p>
<figure id="j_aiht-2024-75-3823_fig_001" position="float" fig-type="figure"><h2>Figure 1</h2>
<figCaption><p>The dependence of experimental <italic>E</italic><sub>p1</sub> (pH = 7) on 
<inline-formula>
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<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
, calculated using the PM6 method, for 14 flavonoids from (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>). Empty circle represents 
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<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
 of hesperetin calculated using methoxy group planar with the B ring plane [as in (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>)]. When the methoxy group was set orthogonally to the B ring plane (filled circle), the 
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<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
 of hesperetin fit the regression model, yielding <italic>R</italic><sup>2</sup>=0.930, SE=0.053, and SE<sub>cv</sub>=0.069</p></figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_fig_001.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/660590071ae47050093cd9ef/j_aiht-2024-75-3823_fig_001.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240722T142137Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240722%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=f4e5a00478058dbd45f8af8c78a09278c25b21e2af95f253ba66776e1568a6c0" class="mw-100"/>
</figure>
<p><a ref-type="fig" href="#j_aiht-2024-75-3823_fig_001">Figures 1</a> and <a ref-type="fig" href="#j_aiht-2024-75-3823_fig_002">2</a> show that 
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<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
 values for hesperetin calculated in this way fit the quadratic regression models in (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>).</p>
<figure id="j_aiht-2024-75-3823_fig_002" position="float" fig-type="figure"><h2>Figure 2</h2>
<figCaption><p>The dependence of experimental relative AA mean on 
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<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
, calculated using the PM6 method for the set of 14 flavonoids from (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>). Empty circle represents 
<inline-formula>
<alternatives>
<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
 of hesperetin calculated using methoxy group planar with the B ring plane [as in (<a ref-type="bibr" href="#j_aiht-2024-75-3823_ref_001">1</a>)]. When the methoxy group was set orthogonally to the B ring plane (filled circle), the 
<inline-formula>
<alternatives>
<inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_ineq_001.png"></inline-graphic>
<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mstyle displaystyle="true"><munder><mo>∑</mo><mrow><mtext>s</mtext><mo stretchy="false">(</mo><mtext>C</mtext><mo stretchy="false">)</mo></mrow></munder><mrow><msub><mrow><mtext>AOSP</mtext></mrow><mrow><mtext>Rad</mtext></mrow></msub></mrow></mstyle></math>
<tex-math>\sum\limits_{{\rm{s}}({\rm{C}})} {{\rm{AOSP}}_{{\rm{Rad}}} } </tex-math>
</alternatives>
</inline-formula>
 of hesperetin fit the regression model well, yielding <italic>R</italic><sup>2</sup>=0.942, SE=0.059, and SE<sub>cv</sub>=0.073 (after exclusion of quercetin)</p></figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_aiht-2024-75-3823_fig_002.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/660590071ae47050093cd9ef/j_aiht-2024-75-3823_fig_002.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240722T142137Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240722%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=435206712d7d6f687a40435355dfa0f95401a377eb13ac91a0e9ef5570fc9e8b" class="mw-100"/>
</figure>
</div>

A follow-up on the hesperetin issue in modelling the first electrochemical oxidation potential and antioxidant activity of flavonoids

Archives of Industrial Hygiene and Toxicology

This work is licensed under the Creative Commons Attribution 4.0 International License.

A follow-up on the hesperetin issue in modelling the first electrochemical oxidation potential and antioxidant activity of flavonoids

Article Category: Letter to the Editor

Published Online: Mar 29, 2024

Page range: 85 - 86

DOI: https://doi.org/10.2478/aiht-2024-75-3823

© 2024 Ante Miličević, published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.