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Cyclooxygenase-1

Cyclooxygenase-1 (COX-1), also known as prostaglandin G/H synthase 1 (PTGS1), is a constitutively expressed enzyme that catalyzes the committed first two steps in the biosynthesis of prostanoids from arachidonic acid, converting it first to the endoperoxide prostaglandin G₂ (PGG₂) via cyclooxygenation and then to prostaglandin H₂ (PGH₂) through peroxidation.^[1] This process occurs at the endoplasmic reticulum and nuclear envelope, where PGH₂ serves as a precursor for bioactive lipid mediators including prostaglandins, thromboxanes, and prostacyclins, which regulate diverse physiological functions.^[2] As a key component of the housekeeping arachidonic acid cascade, COX-1 maintains basal prostanoid levels essential for homeostasis throughout the body.^[3] Structurally, COX-1 is a homodimeric monotopic membrane protein with a molecular weight of approximately 70 kDa, comprising 599 amino acids encoded by the PTGS1 gene on chromosome 9q33.2; each monomer features an N-terminal epidermal growth factor-like domain, a central membrane-binding domain with four transmembrane helices, and a C-terminal catalytic domain housing the cyclooxygenase active site (near Tyr-385) and peroxidase active site.^[4]^[5] The enzyme requires activation by a tyrosyl radical for catalysis and exhibits narrower substrate specificity compared to its isoform, with optimal activity under higher hydroperoxide conditions.^[1] First identified in the early 1970s as the primary target of non-steroidal anti-inflammatory drugs (NSAIDs) through studies on aspirin inhibition, COX-1 was purified in 1976 and molecularly cloned in 1988, revealing its distinction from the inducible COX-2 isoform discovered shortly thereafter.^[2] In physiology, COX-1-derived prostanoids play critical roles in cytoprotection of the gastric mucosa, promotion of platelet aggregation and hemostasis via thromboxane A₂, and regulation of renal perfusion and vascular tone; its ubiquitous, stable expression contrasts with the inflammation-inducible COX-2, making COX-1 inhibition a common cause of NSAID-associated gastrointestinal toxicity.^[3] While traditionally viewed as a "housekeeping" enzyme, emerging evidence also links COX-1 to pathological processes such as certain cancers and neuroinflammation, underscoring its broader therapeutic relevance.^[4]

Discovery and Molecular Biology

History and Nomenclature

The enzymatic activity of cyclooxygenase-1 (COX-1), initially known as the fatty acid cyclooxygenase or prostaglandin synthase, was first isolated and characterized in the 1960s through studies on the biosynthesis of prostaglandins from arachidonic acid. In 1964, D.A. van Dorp and colleagues demonstrated the enzymatic conversion of polyunsaturated fatty acids, such as arachidonic acid, into prostaglandins using microsomal preparations from sheep vesicular glands, establishing the gland as a rich source for the enzyme. Bengt Samuelsson's group extended this work in 1967 by detailing the oxygenation mechanism, showing that the enzyme inserts two oxygen molecules to form a cyclic endoperoxide intermediate, prostaglandin G2 (PGG2), in a process termed cyclooxygenation. These early biochemical assays relied on radio-labeled arachidonic acid substrates and thin-layer chromatography to measure product formation, confirming the enzyme's role in the initial committed step of prostanoid synthesis. Purification efforts in the 1970s advanced the understanding of COX-1 as a membrane-bound, heme-dependent enzyme. In 1976, M. Hemler and W.E.M. Lands achieved significant purification from sheep vesicular gland microsomes using detergent solubilization (e.g., Tween-40), ammonium sulfate precipitation, and chromatography, yielding an enzyme preparation with approximately 200 units/mg protein activity and revealing two forms of iron (heme and non-heme) in the holoenzyme. Concurrently, T. Miyamoto et al. purified the enzyme from bovine vesicular glands, separating it into solubilized fractions that retained both cyclooxygenase and peroxidase activities essential for converting PGG2 to prostaglandin H2 (PGH2). These methods highlighted the enzyme's instability and requirement for hematin activation, laying the groundwork for structural studies. Sheep vesicular glands remained the preferred tissue due to their high COX-1 expression and ease of extraction. The molecular cloning of the COX-1 gene, officially symbolized as PTGS1 (prostaglandin-endoperoxide synthase 1), occurred in 1988, marking a pivotal advancement. D.L. DeWitt and W.L. Smith isolated and sequenced the complementary DNA (cDNA) from sheep vesicular gland mRNA, deducing the primary structure of the 600-amino-acid protein and confirming its bifunctional nature. Independently, C. Yokoyama, T. Takai, and T. Tanabe reported the sheep sequence and cloned the human PTGS1 homolog from endothelial cells, revealing 91% amino acid identity between species. The human PTGS1 gene is located on chromosome 9q33.2, spanning about 25 kb with 11 exons. These cloning efforts used oligonucleotide probes based on partial amino acid sequences from purified protein and expression in Xenopus oocytes or COS cells to verify activity.^[6] Nomenclature for the enzyme evolved alongside these discoveries to reflect its catalytic properties and distinction from related isoforms. Initially termed "prostaglandin endoperoxide synthase" (PGES or PGHS) to emphasize its endoperoxide-forming peroxidase activity, the name shifted to "cyclooxygenase" in the 1970s to underscore the unique cyclization and dioxygenation of arachidonic acid at the active site. Following the 1991 cloning of the inducible isoform (later COX-2), the constitutive form was specifically designated COX-1 to differentiate their expression patterns and roles, with PTGS1 as the approved gene symbol by the Human Genome Organization. This naming convention facilitated targeted research into isoform-specific inhibitors. The distinction from COX-2, encoded by PTGS2 on chromosome 1, highlights COX-1's housekeeping functions versus COX-2's inflammation-associated induction.

Gene Structure and Isozymes

The PTGS1 gene, which encodes the cyclooxygenase-1 (COX-1) enzyme, is located on the long arm of human chromosome 9 at q33.2 and spans approximately 25 kb in length.^[7] It consists of 11 exons that are interrupted by 10 introns, with the canonical mRNA transcript (ENST00000362012) measuring about 2.8 kb.^[8] The promoter region of PTGS1 lacks a canonical TATA box or CAAT box but includes multiple regulatory elements, such as binding sites for the transcription factor Sp1, which contribute to its constitutive expression pattern. These structural features were first elucidated through genomic cloning efforts in the late 1980s. COX-1, the protein product of PTGS1, is a constitutively expressed isoform comprising 599 amino acids, playing a housekeeping role in prostaglandin synthesis across various tissues. In contrast, the related isozyme COX-2, encoded by the PTGS2 gene on chromosome 1, is inducible under inflammatory or stress conditions and consists of 604 amino acids, sharing approximately 60% sequence identity with COX-1 but differing in regulatory responsiveness. A third variant, COX-3, arises as a splice variant of a COX-1 paralog (COX-1b) primarily in canine tissues, where it retains enzymatic activity sensitive to analgesics like acetaminophen; however, the human equivalent splice variant produces a truncated, non-functional protein lacking key catalytic domains. Genetic variation in PTGS1 includes common polymorphisms such as the C50T single nucleotide polymorphism (rs3842787) in the proximal promoter region, which has been linked to modulated gene expression levels and potential influences on enzyme activity in response to stimuli. Other variants, like -842A>G, similarly affect transcriptional efficiency by altering transcription factor binding. The PTGS1 sequence exhibits strong evolutionary conservation across mammalian species, with over 90% identity in coding regions between humans and rodents, underscoring its essential role in conserved physiological pathways.

Protein Structure and Catalytic Mechanism

Tertiary Structure and Active Sites

Cyclooxygenase-1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (PTGS1), is a homodimeric integral membrane glycoprotein with each monomer approximately 70 kDa in size. The enzyme is embedded in the endoplasmic reticulum and nuclear envelope membranes, where it functions as a bifunctional catalyst. The three-dimensional structure, first determined for the ovine ortholog at 3.5 Å resolution, reveals a monomeric architecture comprising three distinct domains: an N-terminal epidermal growth factor (EGF)-like domain (residues 34–72), a membrane-binding domain (residues 73–116) consisting of four amphipathic α-helices that facilitate non-covalent association with the lipid bilayer, and a large C-terminal catalytic domain (residues 117–587) dominated by a barrel-like arrangement of 23 α-helices surrounding four antiparallel β-sheets. This catalytic domain houses both the cyclooxygenase and peroxidase active sites, with the overall fold conserved across species, as confirmed by the recent 3.36 Å crystal structure of human COX-1. The homodimer interface is primarily mediated by interactions between the EGF-like domains and the catalytic domains of opposing monomers, ensuring stability and cooperative function.^[9] The peroxidase active site is located near the protein surface within the catalytic domain, centered around a heme prosthetic group axially ligated by a proximal histidine (His-388). Key residues in the distal heme pocket include His-207, which serves as the conserved distal histidine facilitating peroxide substrate binding and reduction, and Trp-199, which participates in long-range electron transfer to support the peroxidase cycle. This site enables the reduction of hydroperoxides to alcohols, generating oxidized intermediates essential for catalysis. In contrast, the cyclooxygenase active site is a narrow, L-shaped hydrophobic channel approximately 25 Å long, extending from the membrane-binding domain into the catalytic core. The channel apex features Tyr-385, the catalytic residue that forms a tyrosyl radical to initiate fatty acid abstraction, and Ser-530, which coordinates substrate carboxylate groups and is the site of irreversible acetylation by aspirin. The channel's constriction, formed by residues like Arg-120 and Val-523, regulates access for arachidonic acid, with the hydrophobic lining (e.g., Leu-384, Phe-518) accommodating the substrate's acyl chain.^[9] Post-translational modifications are critical for COX-1 folding, stability, and trafficking. The enzyme undergoes N-linked glycosylation at three conserved sites—Asn-53, Asn-144, and Asn-410—in the mature human protein, with oligosaccharide chains contributing approximately 10 kDa to the monomer mass and aiding in endoplasmic reticulum retention and dimerization. Additionally, the EGF-like domain contains three intramolecular disulfide bonds (Cys-37–Cys-47, Cys-41–Cys-57, and Cys-69–Cys-79, using ovine numbering adjusted for human), which stabilize the compact fold and promote inter-monomer interactions. These covalent modifications occur co-translationally in the endoplasmic reticulum, where the oxidative environment supports disulfide formation.^[5]^[10]^[11]

Enzymatic Reaction Pathway

Cyclooxygenase-1 (COX-1), also known as prostaglandin endoperoxide H synthase-1 (PGHS-1), catalyzes the committed step in prostanoid biosynthesis by converting arachidonic acid to prostaglandin H2 (PGH2) via two linked enzymatic activities: a bis-oxygenase (cyclooxygenase) reaction and a peroxidase reaction. The overall transformation incorporates two molecules of oxygen into arachidonic acid (C_{20}H_{32}O_2) to yield PGH2 (C_{20}H_{32}O_4), with the equation arachidonic acid + 2 O_2 → PGG_2 for the cyclooxygenase step, followed by PGG_2 + 2 e^- + 2 H^+ → PGH_2 for the peroxidase step.^[12]^[13] The cyclooxygenase activity initiates catalysis at the hydrophobic active site, where a tyrosyl radical at residue Tyr-385 abstracts the pro-S hydrogen atom from carbon 13 (C-13) of arachidonic acid, generating a delocalized pentadienyl radical intermediate. This radical subsequently adds molecular oxygen at C-11 to form a peroxyl radical, which cyclizes via formation of a C-8 to C-12 endoperoxide bond, transferring the radical to C-8; a second cyclization then establishes the five-membered cyclopentane ring, followed by oxygenation at C-15 to produce the endoperoxide intermediate PGG2, with concomitant regeneration of the Tyr-385 radical to allow multiple turnovers.^[12]^[14] The peroxidase activity occurs at a distinct heme-containing site and reduces the 15-hydroperoxyl group of PGG2 to an alcohol, yielding PGH2. This involves the heme iron cycling through oxidation states: Compound I (a ferryl-oxo porphyrin π-cation radical) abstracts an electron from PGG2 to form Compound II (ferryl-oxo species), which accepts a second electron to complete the reduction, thereby linking the two activities by regenerating the Tyr-385 radical essential for the cyclooxygenase step.^[12]^[14] Kinetically, COX-1 displays a Michaelis constant (K_m) of approximately 5 μM for arachidonic acid, reflecting efficient substrate binding under physiological conditions. However, the enzyme undergoes suicide inactivation after about 100 catalytic turnovers, primarily due to self-oxidation and covalent modification of active site residues during the radical-mediated process.^[15]^[16]

Biological Functions and Regulation

Prostaglandin Biosynthesis and Cellular Roles

Cyclooxygenase-1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (PTGS1), catalyzes the conversion of arachidonic acid to prostaglandin H2 (PGH2), the central precursor in the biosynthesis of various prostanoids. This reaction occurs following the release of arachidonic acid from membrane phospholipids by phospholipase A2 (PLA2), integrating COX-1 into the broader eicosanoid signaling network. PGH2 is then rapidly metabolized by downstream terminal synthases to produce bioactive prostaglandins, including prostaglandin E2 (PGE2) via microsomal prostaglandin E synthase-1 (mPGES-1) or other PGE synthases, prostaglandin D2 (PGD2) via prostaglandin D synthases, prostaglandin F2α (PGF2α) via PGF synthase, prostacyclin (PGI2) via prostacyclin synthase, and thromboxane A2 (TXA2) via thromboxane A synthase. These transformations occur in a cell- and tissue-specific manner, reflecting COX-1's constitutive expression and its role in basal prostanoid production for housekeeping functions. In cellular contexts, COX-1-derived PGE2 plays a critical role in maintaining gastric mucosal integrity by promoting mucus and bicarbonate secretion, enhancing epithelial barrier function, and modulating blood flow to prevent damage from luminal acids. Similarly, TXA2 synthesized via the COX-1 pathway in platelets induces shape change, aggregation, and degranulation, facilitating hemostasis and thrombus formation. In the kidney, COX-1-mediated TXA2 production contributes to the regulation of renal blood flow through vasoconstrictive effects on glomerular arterioles, balancing the vasodilatory actions of other prostanoids like PGE2 and PGI2 to maintain glomerular filtration under basal conditions. The basal activity of COX-1 ensures steady-state production of these prostanoids, supporting essential cellular homeostasis such as cytoprotection and vascular tone without the need for external stimuli, distinguishing it from inducible pathways. This constitutive coupling with PLA2 and downstream synthases underscores COX-1's integration into the eicosanoid network, where disruptions can impair immediate cellular signaling and physiological balance.

Expression Patterns and Regulatory Mechanisms

Cyclooxygenase-1 (COX-1), encoded by the PTGS1 gene, displays ubiquitous basal expression in most mammalian tissues, reflecting its role as a housekeeping enzyme that supports constitutive prostaglandin production for physiological maintenance.^[17] High levels of COX-1 are particularly noted in the gastric mucosa, where it contributes to mucosal protection; in the kidney, aiding renal blood flow and salt balance; and in platelets, facilitating thromboxane A2 synthesis for hemostasis.^[18] This steady-state pattern contrasts sharply with cyclooxygenase-2 (COX-2), which exhibits minimal basal expression but undergoes rapid transcriptional induction in response to proinflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, enabling acute inflammatory responses.^[19] Unlike COX-2, COX-1 maintains consistent mRNA and protein levels due to their inherent stability, without prominent reliance on destabilizing elements like AU-rich sequences in the 3' untranslated region.^[20] Transcriptional regulation of COX-1 expression is primarily governed by housekeeping gene features, including a TATA-less promoter with high GC content and multiple Sp1 binding sites that drive basal activity and responsiveness to stimuli.^[20] For instance, the Sp1 sites at positions -610, -111, and -89 are critical for phorbol 12-myristate 13-acetate (PMA)-induced upregulation in megakaryocytic cells, while an AP-1 site in intron 8 cooperates with the -111 Sp1 site to enhance transcription during cellular differentiation.^[20] Additional inducers include shear stress in endothelial cells, bradykinin in smooth muscle, and estrogen in vascular tissues, underscoring tissue-specific modulation without the broad cytokine-driven surges seen in COX-2.^[20] In certain inflammatory contexts, such as tobacco carcinogen exposure in macrophages, NF-κB activation can contribute to COX-1 induction, though this is less dominant than for COX-2.^[21] Glucocorticoids exert cell-type-dependent effects on COX-1 transcription via the glucocorticoid receptor, often repressing expression to fine-tune prostaglandin levels. In fetal pulmonary artery endothelial cells, dexamethasone reduces COX-1 mRNA by up to 50% and protein by 44% within 48 hours, leading to decreased prostacyclin synthesis, an effect reversed by glucocorticoid receptor antagonists like mifepristone.^[22] Conversely, in cardiomyocytes and neuroblastoma cells, glucocorticoids can elevate COX-1 levels, highlighting contextual variability in regulatory outcomes.^[23] Post-transcriptional mechanisms are limited, with COX-1 mRNA stability ensuring sustained expression, though specific microRNA interactions, such as with miR-146a, show no significant impact on COX-1 unlike their prominent role in destabilizing COX-2 transcripts.^[24] Prostaglandin-mediated feedback, while well-documented for COX-2, lacks clear evidence of direct inhibitory control over COX-1 levels, maintaining its constitutive profile.^[20]

Physiological and Pathophysiological Roles

Homeostatic Functions in Tissues

Cyclooxygenase-1 (COX-1) plays a pivotal role in maintaining gastrointestinal mucosal integrity through the constitutive production of prostaglandins, particularly prostaglandin E2 (PGE2), which stimulates the secretion of mucus and bicarbonate by epithelial cells. This cytoprotective mechanism helps neutralize gastric acid and forms a physical barrier against luminal irritants, thereby preventing erosion and ulceration of the gastric mucosa. Studies in COX-1-deficient models demonstrate increased susceptibility to gastric injury, underscoring the enzyme's essential function in basal mucosal defense.^[25]^[26] Additionally, COX-1-derived PGE2 and prostacyclin (PGI2) regulate mucosal blood flow, ensuring nutrient delivery and rapid removal of acid, which further supports tissue homeostasis in the stomach and intestines.^[25] In the cardiovascular system, COX-1 is constitutively expressed in platelets, where it catalyzes the conversion of arachidonic acid to prostaglandin H2 (PGH2), which is then transformed into thromboxane A2 (TXA2) by thromboxane synthase. TXA2 promotes platelet activation, shape change, and aggregation by binding to thromboxane-prostanoid (TP) receptors, facilitating primary hemostasis and clot formation at sites of vascular injury. This process is amplified through autocrine and paracrine signaling, with TXA2 also inducing vasoconstriction to reduce blood loss.^[27] Complementing this, COX-1 in endothelial cells produces PGI2, which counterbalances TXA2 by promoting vasodilation and inhibiting platelet aggregation, thereby maintaining vascular tone and preventing excessive thrombosis under normal conditions.^[28] COX-1 contributes to renal homeostasis primarily by supporting glomerular filtration rate (GFR) through the production of vasodilatory prostaglandins, such as PGI2, in mesangial and endothelial cells of the afferent arterioles. This is particularly crucial in states of reduced renal perfusion, where COX-1-derived prostanoids counteract vasoconstrictive influences to preserve blood flow and filtration.^[29] In COX-1 deficiency, enhanced natriuresis occurs, indicating a role in modulating sodium excretion, likely via indirect effects on tubular function and hemodynamics.^[30] Beyond the kidney, COX-1 supports bone remodeling by generating basal levels of prostaglandins that influence osteoblast and osteoclast activity, maintaining bone turnover balance in response to mechanical and humoral signals.^[31] In female reproduction, COX-1 regulates ovarian follicle maturation and lifespan; its inhibition delays the transition from primary to secondary follicles, thereby prolonging the postnatal ovarian reserve and supporting reproductive longevity.^[32]

Involvement in Diseases and Disorders

Cyclooxygenase-1 (COX-1) plays a significant role in chronic inflammatory conditions by contributing to the sustained production of proinflammatory prostaglandins in affected tissues. In models of rheumatoid arthritis, such as the K/BxN serum-transfer arthritis, COX-1 predominates over COX-2 in generating proinflammatory prostanoids, with COX-1-deficient mice exhibiting full resistance to disease development and reduced joint inflammation.^[33] This suggests that COX-1-mediated prostaglandin synthesis, including potential contributions to prostaglandin E2 (PGE2) levels in synovial tissues, sustains inflammatory responses in autoimmune arthritis. Similarly, in colorectal cancer, COX-1 is constitutively expressed in both normal colonic epithelium and tumor tissues, where it catalyzes the production of malondialdehyde, a mutagen implicated in early carcinogenesis and tumor initiation.^[34] Expression levels of COX-1 vary in advanced colorectal tumors (Dukes' C stage), indicating its potential involvement in disease progression through ongoing prostaglandin-mediated signaling that supports tumor growth.^[35] In cardiovascular diseases, COX-1-derived thromboxane A2 (TXA2) from activated platelets enhances platelet aggregation and vasoconstriction, promoting thrombosis and contributing to the pathogenesis of atherosclerosis.^[36] Elevated TXA2 activity is associated with increased risk of thrombotic events, including plaque instability and vessel occlusion in atherosclerotic lesions.^[36] Genetic polymorphisms in the COX-1 gene have been linked to altered vascular outcomes, with certain variants associated with a higher incidence of myocardial infarction and other cardiovascular events in at-risk populations.^[37] Beyond these, dysregulation of COX-1 activity is implicated in other disorders, particularly through disruptions in its homeostatic prostaglandin production. Over-inhibition of COX-1 impairs gastric mucosal defense by reducing protective prostaglandins, leading to increased susceptibility to gastroduodenal ulcers via diminished mucus and bicarbonate secretion.^[38] In neurodegenerative diseases like Alzheimer's, COX-1 contributes to neuroinflammatory responses triggered by beta-amyloid, where its deficiency reduces microglial activation, oxidative stress, and neuronal damage, suggesting that excessive COX-1 activity exacerbates pathology potentially through loss of balanced neuroprotection.^[39]

Clinical and Therapeutic Aspects

Inhibition by Drugs and NSAIDs

Cyclooxygenase-1 (COX-1) is inhibited by various nonsteroidal anti-inflammatory drugs (NSAIDs) through mechanisms that target its active site, where arachidonic acid binds as the substrate. Aspirin exerts irreversible inhibition by acetylating Serine-530 (Ser-530) within the COX-1 active site, preventing substrate access and permanently inactivating the enzyme until new protein synthesis occurs.^[40] This covalent modification relies on the carboxylate group of aspirin facilitating intramolecular catalysis, with Tyrosine-385 playing a key role in the process.^[40] In contrast, ibuprofen acts as a reversible, competitive inhibitor by binding to the arachidonic acid site in the COX-1 active site, thereby blocking substrate oxygenation without covalent alteration.^[41] NSAIDs are classified based on their selectivity for COX-1 versus COX-2, with many exhibiting non-selective inhibition that affects both isoforms. Non-selective NSAIDs, such as indomethacin and naproxen, potently inhibit COX-1 with low micromolar IC50 values, for example, indomethacin at approximately 1.3 μM and naproxen at 0.6 μM, contributing to broad anti-inflammatory effects but also increased risk of adverse outcomes.^[42] Aspirin also falls into this category, with an IC50 for COX-1 around 2-5 μM, reflecting its strong but irreversible potency against the enzyme.^[42] Some NSAIDs show preferential selectivity for COX-1 over COX-2, such as piroxicam, which has an IC50 of about 9.4 μM for COX-1 compared to 600 μM for COX-2, indicating over 60-fold preference for COX-1 inhibition.^[42] Inhibition of COX-1 by these drugs leads to reduced prostaglandin synthesis, resulting in notable side effects. The loss of COX-1-derived prostaglandins in the gastric mucosa impairs protective mechanisms like mucus and bicarbonate secretion, increasing the risk of gastrointestinal bleeding and ulceration, particularly with chronic use of non-selective NSAIDs.^[43] Conversely, COX-1 inhibition in platelets blocks thromboxane A2 production, providing antiplatelet effects that prolong bleeding time and offer cardioprotective benefits, as seen with low-dose aspirin therapy.^[44]

Therapeutic Targeting and Recent Advances

Efforts to develop COX-1-sparing drugs, primarily through selective COX-2 inhibitors such as celecoxib, have aimed to minimize gastrointestinal toxicity associated with non-selective NSAIDs that inhibit COX-1 in the gastric mucosa. These agents reduce the risk of ulcers and bleeding by preserving COX-1-mediated prostaglandin production essential for mucosal protection, as demonstrated in clinical studies showing lower incidence of upper GI events compared to traditional NSAIDs.^[45] Nitric oxide-releasing derivatives of aspirin, such as NCX-4016, represent an innovative approach to gastroprotection while maintaining COX-1 inhibition for antiplatelet effects. These compounds release nitric oxide to enhance gastric blood flow and mucus production, counteracting the ulcerogenic potential of aspirin; preclinical and early clinical data indicate they prevent ethanol- and stress-induced gastric damage more effectively than conventional aspirin without compromising cardiovascular benefits.^[46]^[47] Recent advances in the 2020s have explored selective COX-1 inhibitors for cancer therapy, highlighting their role in modulating the tumor microenvironment. Studies have shown that COX-1-dependent prostaglandin pathways contribute to tumor growth and immune evasion, with selective inhibitors like those derived from pyrazolo[1,5-a]pyrimidine scaffolds demonstrating potent anti-proliferative effects in breast cancer models by disrupting arachidonic acid metabolism.^[48]^[49] Pharmacogenomic research on PTGS1 variants has opened avenues for precision medicine in COX-1 modulation, identifying polymorphisms that alter enzyme activity and aspirin responsiveness. For instance, variants like R53H and L237M reduce COX-1 acetylation by aspirin, leading to variable antiplatelet efficacy; genetic testing for these could guide dosing in cardiovascular prevention to optimize outcomes while minimizing bleeding risks.^[50]^[51] Ongoing clinical trials and meta-analyses underscore COX-1 modulation via low-dose aspirin for cardiovascular prevention, with established meta-analyses (e.g., as of 2019, involving over 150,000 participants) indicating a modest reduction in major adverse cardiovascular events (approximately 11-12% relative risk reduction) in primary prevention settings, particularly for those aged 40-59 at elevated risk, though benefits are tempered by bleeding concerns and current guidelines (as of 2025) recommend against routine use in adults aged 60 and older due to net harm from bleeding. Precision approaches incorporating PTGS1 pharmacogenomics are being integrated into trials to personalize aspirin use, aiming to enhance net clinical benefit in diverse populations.^[52]^[53]^[54]

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Physiology, Thromboxane A2 - PubMed
Sep 12, 2022 · Increased activity of TxA2 may play a role in the pathogenesis of myocardial infarction, stroke, atherosclerosis, and bronchial asthma.
[35]
Impacts of COX-1 gene polymorphisms on vascular outcomes in ...
Aug 10, 2014 · The primary endpoint was a composite of nonfatal ischemic stroke, myocardial infarction, and death from cardiovascular causes. ... risk of ...
[36]
Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory ...
The inhibition of COX-1 is believed to be responsible for inducing mucosal injury primarily by impairing prostaglandin-dependent mucosal protective mechanisms.
[37]
Cyclooxygenase-1 Null Mice Show Reduced Neuroinflammation in ...
Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's ...
[38]
Mechanistic insights into cyclooxygenase irreversible inactivation by ...
Ser 530 appears to be acetylated under intramolecular general base catalysis provided by the carboxylate moiety of aspirin, while Tyr 385 plays a crucial role ...
[39]
Differential sensitivity and mechanism of inhibition of COX ... - PubMed
Aug 11, 2009 · Ibuprofen and mefenamic acid are weak, competitive inhibitors of cyclooxygenase-2 (COX-2) oxygenation of arachidonic acid (AA) but potent ...
[40]
Interpreting the clinical significance of the differential inhibition of ...
Most tissues, but particularly platelets, stomach, kidney, Induced by ... Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue ...
[41]
Low-dose aspirin and upper gastrointestinal damage - PubMed
However, due to its action on cyclo-oxygenase (COX), aspirin is associated with upper gastrointestinal (GI) side effects including ulcers and bleeding. Scope: ...
[42]
the antiplatelet action of aspirin and its role in thrombosis treatment ...
This explains the different dosage requirements of aspirin as an antithrombotic (COX-1) and an anti-inflammatory drug (COX-2), respectively. Aspirin is the ...Missing: TXA2 atherosclerosis<|separator|>
[43]
COX Inhibitors - StatPearls - NCBI Bookshelf
COX inhibitors divide into non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) ... NSAIDs include ibuprofen, naproxen, ketorolac, and indomethacin.
[44]
Nitric oxide-releasing aspirin but not conventional aspirin improves ...
The role of NO released from NO-NSAIDs in the mechanism of gastroprotection has been well documented[19-21], but the efficacy of NO-aspirin (ASA) in the healing ...
[45]
Potentially active aspirin derivative to release nitric oxide: In-vitro, in ...
The directly attached NO releasing group can be used to create new, more effective, and safer anti-inflammatory agents. COX-1 is inhibited in the gastric ...
[46]
Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti ... - MDPI
COX-1 expression has been reported to be up-regulated in tumorigenesis [17] and implicated in multiple aspects of cancer pathophysiology and, therefore, the ...
[47]
Synthesis, Inhibitory Activity, and In Silico Modeling of Selective ...
Mar 12, 2021 · The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now ...
[48]
Targeting cancer-related inflammation with non-steroidal anti ...
... role for COX-1 in cancer development remains much less discovered. Several studies showed that COX-1-dependent pathways was required for carcinogenesis, tumor ...
[49]
COX inhibition with anti-PD-1 in advanced dMMR colorectal cancer
Aug 9, 2024 · Wu et al. 1 showed that combining COX inhibitors with PD-1 blockade could be a safe and effective treatment option for dMMR metastatic colorectal cancer.
[50]
Identification and functional characterization of polymorphisms ... - NIH
The gene encoding human COX-1 (PTGS1) has been mapped to chromosome 9q32–q33.3, is approximately 22 kb in length, and contains 11 exons [2,3]. COX-1 is ...
[51]
[PDF] Deep sequencing of PTGS genes reveals genetic susceptibility for ...
The risk haplotype might amplify the effect of COX-1 inhibitors, leading to adverse drug events. • PTGS1 genetic testing shows potential for patients with ...<|separator|>
[52]
A narrative review of research advancements in pharmacogenetics ...
Jul 10, 2025 · Two genes, PTGS1 and PTGS2, encode COX-1 and COX-2, which are enzymes that catalyse the conversion of AA to prostaglandins and thromboxane. Both ...
[53]
Low-dose aspirin for the prevention of atherosclerotic cardiovascular ...
Jun 6, 2024 · The aim of this article is to revisit the role of aspirin in the prevention of atherothrombosis across the cardiovascular risk continuum.Abstract · Introduction
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Pharmacogenomics in Stroke and Cardiovascular Disease: State of ...
Nov 3, 2022 · This review provides an overview of the genetic variants that influence the individual responses to aspirin, clopidogrel, warfarin and statins.