Editing Aspirin (section)

==Mechanism of action==
{{Main|Mechanism of action of aspirin}}
<!-- [[File:PTGS2 inhibited by Aspirin.png|class=skin-invert-image|thumb|Structure of PTGS2 inactivated by aspirin, in the active site of each of the two monomers, serine 530 has been acetylated. Also visible is the salicylic acid that has transferred the acyl group, and the heme cofactor.]] -->

===Discovery of the mechanism===
In 1971, British [[pharmacologist]] [[John Robert Vane]], then employed by the [[Royal College of Surgeons of England|Royal College of Surgeons]] in London, showed that aspirin suppressed the production of [[prostaglandin]]s and [[thromboxane]]s.<ref>{{cite journal | vauthors = Vane JR | title = Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs | journal = Nature | volume = 231 | issue = 25 | pages = 232–5 | date = June 1971 | pmid = 5284360 | doi = 10.1038/newbio231232a0 }}</ref><ref>{{cite journal | vauthors = Vane JR, Botting RM | title = The mechanism of action of aspirin | journal = Thrombosis Research | volume = 110 | issue = 5–6 | pages = 255–8 | date = June 2003 | pmid = 14592543 | doi = 10.1016/s0049-3848(03)00379-7 }}</ref> For this discovery, he was awarded the 1982 [[Nobel Prize in Physiology or Medicine]], jointly with [[Sune Bergström]] and [[Bengt Ingemar Samuelsson]].<ref>{{cite web |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1982/ |title=The Nobel Prize in Physiology or Medicine 1982 |website=Nobelprize.org |url-status=live |archive-url=https://web.archive.org/web/20170627030945/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1982/ |archive-date=27 June 2017}}</ref>

===Prostaglandins and thromboxanes===
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the [[cyclooxygenase]] (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis.{{medical citation needed|date=April 2025}} Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a [[serine]] residue in the active site of the COX enzyme ([[suicide inhibition]]).<ref name="Meek_2010">{{cite journal | vauthors = Meek IL, Van de Laar MA, E Vonkeman H | title = Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks | journal = Pharmaceuticals | volume = 3 | issue = 7 | pages = 2146–2162 | date = July 2010 | pmid = 27713346 | pmc = 4036661 | doi = 10.3390/ph3072146 | doi-access = free }}</ref> This makes aspirin different from other NSAIDs (such as [[diclofenac]] and [[ibuprofen]]), which are reversible inhibitors.<ref name="Meek_2010" />

Low-dose aspirin use irreversibly blocks the formation of [[thromboxane A2|thromboxane A<sub>2</sub>]] in platelets, which inhibits platelet aggregation during the lifetime of the affected platelet (8–9 days). This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack.<ref>{{cite web |url=http://www.americanheart.org/presenter.jhtml?identifier=4456 |title=Aspirin in heart attack and stroke prevention |access-date=8 May 2008 |publisher=American Heart Association |archive-url=https://web.archive.org/web/20080331031146/http://www.americanheart.org/presenter.jhtml?identifier=4456 |archive-date=31 March 2008 }}</ref> 40{{nbsp}}mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A<sub>2</sub> release provoked acutely, with the prostaglandin I<sub>2</sub> synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.<ref>{{cite journal | vauthors = Tohgi H, Konno S, Tamura K, Kimura B, Kawano K | title = Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin | journal = Stroke | volume = 23 | issue = 10 | pages = 1400–3 | date = October 1992 | pmid = 1412574 | doi = 10.1161/01.STR.23.10.1400 | doi-access = free | title-link = doi }}</ref>

Prostaglandins, a type of [[hormone]], have diverse effects, including the transmission of pain information to the brain, modulation of the [[hypothalamus|hypothalamic]] thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form [[clot|blood clots]]. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention to prevent a second acute myocardial infarction.<ref name="pmid19482214">{{cite journal |vauthors=Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A |date=May 2009 |title=Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials |journal=Lancet |volume=373 |issue=9678 |pages=1849–60 |doi=10.1016/S0140-6736(09)60503-1 |pmc=2715005 |pmid=19482214}}</ref>

===COX-1 and COX-2 inhibition===
At least two different types of [[cyclooxygenase]]s, [[COX-1]] and [[COX-2]], are acted on by aspirin. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces [[prostanoid]]s, most of which are proinflammatory. Aspirin-modified COX-2 (aka [[prostaglandin-endoperoxide synthase 2]] or PTGS2) produces [[epi-lipoxin]]s, most of which are anti-inflammatory.<ref>{{cite journal |vauthors=Goel A, Aggarwal S, Partap S, Saurabh A, Choudhary |date=2012 |title=Pharmacokinetic solubility and dissolution profile of antiarrythmic drugs |journal=Int J Pharma Prof Res |volume=3 |issue=1 |pages=592–601}}</ref>{{Verify source|date=August 2016}}<ref>{{cite journal | vauthors = Clària J, Serhan CN | title = Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9475–9479 | date = October 1995 | pmid = 7568157 | doi = 10.1073/pnas.92.21.9475 | doi-access = free | pmc = 40824 | bibcode = 1995PNAS...92.9475C }}</ref> Newer NSAID drugs, [[COX-2 inhibitor]]s (coxibs), have been developed to inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side effects.<ref name=COX2002/>

Several COX-2 inhibitors, such as [[rofecoxib]] (Vioxx), have been withdrawn from the market, after evidence emerged that COX-2 inhibitors increase the risk of heart attack and stroke.<ref>{{cite journal | vauthors = Martínez-González J, Badimon L | title = Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks | journal = Current Pharmaceutical Design | volume = 13 | issue = 22 | pages = 2215–27 | year = 2007 | pmid = 17691994 | doi = 10.2174/138161207781368774 }}</ref><ref>{{cite journal | vauthors = Funk CD, FitzGerald GA | title = COX-2 inhibitors and cardiovascular risk | journal = Journal of Cardiovascular Pharmacology | volume = 50 | issue = 5 | pages = 470–9 | date = November 2007 | pmid = 18030055 | doi = 10.1097/FJC.0b013e318157f72d | s2cid = 39103383 | doi-access = free }}</ref> Endothelial cells lining the microvasculature in the body are proposed to express COX-2, and, by selectively inhibiting COX-2, prostaglandin production (specifically, PGI<sub>2</sub>; prostacyclin) is downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anticoagulative effect of [[PGI2|PGI<sub>2</sub>]] is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems.{{medical citation needed|date=April 2025}}

Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the [[prostaglandins]], converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a [[lipoxygenase]]-like enzyme: aspirin-treated COX-2 metabolizes a variety of [[polyunsaturated fatty acids]] to hydroperoxy products which are then further metabolized to [[specialized proresolving mediators]] such as the [[Epi-lipoxin|aspirin-triggered lipoxins]](15-epilipoxin-A4/B4), aspirin-triggered [[resolvins]], and aspirin-triggered [[maresin]]s. These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin.<ref name="pmid25895638">{{cite journal | vauthors = Romano M, Cianci E, Simiele F, Recchiuti A | title = Lipoxins and aspirin-triggered lipoxins in resolution of inflammation | journal = European Journal of Pharmacology | volume = 760 | pages = 49–63 | date = August 2015 | pmid = 25895638 | doi = 10.1016/j.ejphar.2015.03.083 }}</ref><ref name="pmid23747022">{{cite journal | vauthors = Serhan CN, Chiang N | title = Resolution phase lipid mediators of inflammation: agonists of resolution | journal = Current Opinion in Pharmacology | volume = 13 | issue = 4 | pages = 632–40 | date = August 2013 | pmid = 23747022 | pmc = 3732499 | doi = 10.1016/j.coph.2013.05.012 }}</ref><ref name="pmid26546723">{{cite journal | vauthors = Weylandt KH | title = Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell | journal = European Journal of Pharmacology | volume = 785 | pages = 108–115 | date = August 2016 | pmid = 26546723 | doi = 10.1016/j.ejphar.2015.11.002 }}</ref>

===Additional mechanisms===
Aspirin has been shown to have at least three additional modes of action. It uncouples [[oxidative phosphorylation]] in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons.<ref name="SomasundaramS">{{cite journal | vauthors = Somasundaram S, Sigthorsson G, Simpson RJ, Watts J, Jacob M, Tavares IA, Rafi S, Roseth A, Foster R, Price AB, Wrigglesworth JM, Bjarnason I | title = Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat | journal = Alimentary Pharmacology & Therapeutics | volume = 14 | issue = 5 | pages = 639–50 | date = May 2000 | pmid = 10792129 | doi = 10.1046/j.1365-2036.2000.00723.x | s2cid = 44832283 | doi-access = free | title-link = doi }}</ref> Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show that aspirin helps to fight infection.<ref>{{cite journal | vauthors = Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW | title = 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation | journal = The Journal of Experimental Medicine | volume = 200 | issue = 1 | pages = 69–78 | date = July 2004 | pmid = 15238606 | pmc = 2213311 | doi = 10.1084/jem.20040566 }}</ref> More recent data also suggest salicylic acid and its derivatives modulate signalling through [[NF-κB]].<ref>{{cite journal | vauthors = McCarty MF, Block KI | title = Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy | journal = Integrative Cancer Therapies | volume = 5 | issue = 3 | pages = 252–68 | date = September 2006 | pmid = 16880431 | doi = 10.1177/1534735406291499 | doi-access = free | title-link = doi }}</ref> NF-κB, a [[transcription factor]] complex, plays a central role in many biological processes, including inflammation.<ref>{{cite journal | vauthors = Silva Caldas AP, Chaves LO, Linhares Da Silva L, De Castro Morais D, Gonçalves Alfenas RD |date=29 December 2017|title=Mechanisms involved in the cardioprotective effect of avocado consumption: A systematic review|journal=International Journal of Food Properties|volume=20|issue=sup2|pages=1675–1685 |doi=10.1080/10942912.2017.1352601 |issn=1094-2912|quote=...there was postprandial reduction on the plasma concentration of IL-6 and IkBα preservation, followed by the lower activation of NFκB, considered the main transcription factor capable of inducing inflammatory response by stimulating the expression of proinflammatory cytokines, chemokines, and adhesion molecules.|doi-access=free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L | title = Inflammatory responses and inflammation-associated diseases in organs | journal = Oncotarget | volume = 9 | issue = 6 | pages = 7204–7218 | date = January 2018 | pmid = 29467962 | pmc = 5805548 | doi = 10.18632/oncotarget.23208 }}</ref><ref>{{cite journal | vauthors = Lawrence T | title = The nuclear factor NF-kappaB pathway in inflammation | journal = Cold Spring Harbor Perspectives in Biology | volume = 1 | issue = 6 | pages = a001651 | date = December 2009 | pmid = 20457564 | pmc = 2882124 | doi = 10.1101/cshperspect.a001651 }}</ref>

Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate [[AMP-activated protein kinase]], which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin.<ref>{{cite journal | vauthors = Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG | title = The ancient drug salicylate directly activates AMP-activated protein kinase | journal = Science | volume = 336 | issue = 6083 | pages = 918–22 | date = May 2012 | pmid = 22517326 | pmc = 3399766 | doi = 10.1126/science.1215327 | bibcode = 2012Sci...336..918H }}</ref><ref>{{cite journal |title=Clues to aspirin's anti-cancer effects revealed |journal=New Scientist |date=28 April 2012 |volume=214 |issue=2862 |pages=16 |doi=10.1016/S0262-4079(12)61073-2 }}</ref> The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes.<ref>{{cite journal | vauthors = Alfonso LF, Srivenugopal KS, Arumugam TV, Abbruscato TJ, Weidanz JA, Bhat GJ | title = Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells | journal = International Journal of Oncology | volume = 34 | issue = 3 | pages = 597–608 | date = March 2009 | pmid = 19212664 | doi = 10.3892/ijo_00000185 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Alfonso LF, Srivenugopal KS, Bhat GJ | title = Does aspirin acetylate multiple cellular proteins? (Review) | journal = Molecular Medicine Reports | volume = 2 | issue = 4 | pages = 533–7 | year = 2009 | pmid = 21475861 | doi = 10.3892/mmr_00000132 | type = review | doi-access = free | title-link = doi }}</ref> These acetylation reactions may explain many hitherto unexplained effects of aspirin.<ref>{{cite journal | vauthors = Alfonso LF, Srivenugopal KS, Bhat GJ | title = Does aspirin acetylate multiple cellular proteins? (Review) | journal = Molecular Medicine Reports | volume = 2 | issue = 4 | pages = 533–537 | date = 4 June 2009 | pmid = 21475861 | doi = 10.3892/mmr_00000132 | doi-access = free }}</ref>