Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition?
Abstract The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT’s analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-08-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.835 |
| _version_ | 1818881217119911936 |
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| author | Christopher J. Esh Bryna C. R. Chrismas Alexis R. Mauger Lee Taylor |
| author_facet | Christopher J. Esh Bryna C. R. Chrismas Alexis R. Mauger Lee Taylor |
| author_sort | Christopher J. Esh |
| collection | DOAJ |
| description | Abstract The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT’s analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. COX variants have been sequenced among various mammalian species including humans. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT’s mechanism of action. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. ACT may selectively inhibit COX2, with evidence of a 4.4‐fold greater COX2 inhibition than COX1. However, this is markedly lower than other available selective COX2 inhibitors (up to 433‐fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform; (ii) is not selective in its COX inhibition; and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. Robust research designs are required in humans to objectively confirm these hypotheses. |
| first_indexed | 2024-12-19T14:58:21Z |
| format | Article |
| id | doaj.art-3deb29cb797d4cf3addbc900938cb1ff |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-19T14:58:21Z |
| publishDate | 2021-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-3deb29cb797d4cf3addbc900938cb1ff2022-12-21T20:16:38ZengWileyPharmacology Research & Perspectives2052-17072021-08-0194n/an/a10.1002/prp2.835Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition?Christopher J. Esh0Bryna C. R. Chrismas1Alexis R. Mauger2Lee Taylor3Aspetar—Qatar Orthopaedic and Sports Medicine HospitalResearch and Scientific SupportAspire Zone Doha QatarDepartment of Physical Education College of Education Qatar University Doha QatarEndurance Research Group School of Sport and Exercise Sciences University of Kent Chatham Maritime UKSchool of Sport, Exercise and Health Sciences Loughborough University Loughborough UKAbstract The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT’s analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. COX variants have been sequenced among various mammalian species including humans. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT’s mechanism of action. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. ACT may selectively inhibit COX2, with evidence of a 4.4‐fold greater COX2 inhibition than COX1. However, this is markedly lower than other available selective COX2 inhibitors (up to 433‐fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform; (ii) is not selective in its COX inhibition; and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. Robust research designs are required in humans to objectively confirm these hypotheses.https://doi.org/10.1002/prp2.835acetaminophenarachidonic acidcyclooxygenasemechanism of action |
| spellingShingle | Christopher J. Esh Bryna C. R. Chrismas Alexis R. Mauger Lee Taylor Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? Pharmacology Research & Perspectives acetaminophen arachidonic acid cyclooxygenase mechanism of action |
| title | Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? |
| title_full | Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? |
| title_fullStr | Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? |
| title_full_unstemmed | Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? |
| title_short | Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? |
| title_sort | pharmacological hypotheses is acetaminophen selective in its cyclooxygenase inhibition |
| topic | acetaminophen arachidonic acid cyclooxygenase mechanism of action |
| url | https://doi.org/10.1002/prp2.835 |
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