Esh, Taylor (2021) Pharmacological Hypotheses - Is acetaminophen selective in its cyclooxygenase inhibition.pdf (664.72 kB)

Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition?

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journal contribution
posted on 14.09.2021, 08:39 by Christopher J Esh, Bryna C. R. Chrismas, Alexis R. Mauger, Lee TaylorLee Taylor
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.

History

School

  • Sport, Exercise and Health Sciences

Published in

Pharmacology Research and Perspectives

Volume

9

Issue

4

Publisher

JOHN WILEY & SONS LTD

Version

VoR (Version of Record)

Rights holder

© The authors

Publisher statement

This is an Open Access Article. It is published by Wiley under the Creative Commons Attribution 4.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/

Acceptance date

04/06/2021

Publication date

2021-07-18

Copyright date

2021

ISSN

2052-1707

eISSN

2052-1707

Language

en

Depositor

Dr Lee Taylor. Deposit date: 7 September 2021

Article number

e00835