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Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacological...

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Autores principales: Pouncey, Dakota L., Barnette, Dustyn A., Sinnott, Riley W., Phillips, Sarah J., Flynn, Noah R., Hendrickson, Howard P., Swamidass, S. Joshua, Miller, Grover P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8793337/
https://www.ncbi.nlm.nih.gov/pubmed/35095511
http://dx.doi.org/10.3389/fphar.2021.805133
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author Pouncey, Dakota L.
Barnette, Dustyn A.
Sinnott, Riley W.
Phillips, Sarah J.
Flynn, Noah R.
Hendrickson, Howard P.
Swamidass, S. Joshua
Miller, Grover P.
author_facet Pouncey, Dakota L.
Barnette, Dustyn A.
Sinnott, Riley W.
Phillips, Sarah J.
Flynn, Noah R.
Hendrickson, Howard P.
Swamidass, S. Joshua
Miller, Grover P.
author_sort Pouncey, Dakota L.
collection PubMed
description Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.
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spelling pubmed-87933372022-01-28 Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin Pouncey, Dakota L. Barnette, Dustyn A. Sinnott, Riley W. Phillips, Sarah J. Flynn, Noah R. Hendrickson, Howard P. Swamidass, S. Joshua Miller, Grover P. Front Pharmacol Pharmacology Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism. Frontiers Media S.A. 2022-01-13 /pmc/articles/PMC8793337/ /pubmed/35095511 http://dx.doi.org/10.3389/fphar.2021.805133 Text en Copyright © 2022 Pouncey, Barnette, Sinnott, Phillips, Flynn, Hendrickson, Swamidass and Miller. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Pouncey, Dakota L.
Barnette, Dustyn A.
Sinnott, Riley W.
Phillips, Sarah J.
Flynn, Noah R.
Hendrickson, Howard P.
Swamidass, S. Joshua
Miller, Grover P.
Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
title Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
title_full Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
title_fullStr Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
title_full_unstemmed Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
title_short Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
title_sort discovery of novel reductive elimination pathway for 10-hydroxywarfarin
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8793337/
https://www.ncbi.nlm.nih.gov/pubmed/35095511
http://dx.doi.org/10.3389/fphar.2021.805133
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