Conclusions
| . | COX-1 . | COX-2 . |
| cDNA | Chromosome 9; 22 kB | Chromosome 1; 8.3 kB |
| mRNA | 2.8 kB | 4.5 kB |
| Protein | 72 kDa: 599 amino acids | 72 kDa: 604 amino acids |
| Homology | Amino acids: 90% between species for bot ... | Amino acids: 90% between species for bot ... |
What does Cox 2 stand for?
This makes sense as COX-2 is found more commonly in inflammatory and immune cells than COX-1 drugs. Unfortunately, this would prove to be far, far from the truth. While COX-2 is more specific to inflammation, the side effects can be worse than COX-1 drugs. NSAID Side Effects. The side effects of COX-1 drugs are pretty terrible.
Is naproxen a COX 2 inhibitor?
Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective coxib. This results in the inhibition of prostaglandin synthesis. Prostaglandins act as signaling molecules in the body, inducing inflammation. Thus, by inhibiting COX-1/2, naproxen induces an anti-inflammatory effect. Pharmacokinetics
What is the difference between tax 1 and tax 2?
But tax clarity is ... discount valid for the next two weeks. Congestion on the Ethereum network and volatile swings in gas fees have thrown the topic of Layer 1 and Layer 2 ecosystems back under the spotlight. What is the difference between the two?
What does Cox 1 do?
- How does COX-1 cause platelet aggregation?
- Do platelets synthesize COX-1?
- What is the role of COX-1?
- What kind of prostaglandins are synthesized by COX-1 and COX-2 enzymes?
- What prostaglandins does COX-1 make?
- Where is COX-1 produced?
- Is COX-1 in the brain?
- Is thromboxane a prostaglandin?
- Is thromboxane A2 a vasoconstrictor?
What is the difference between COX-1 and COX-2?
COX-1 is thought to be responsible for the production of prostaglandins associated with normal physiologic function and is found in such tissues as the stomach, kidney, and platelets. COX-2 was thought to be induced as the result of inflammation and responsible for producing prostaglandins such as prostaglandin E2.
What do COX-1 and COX-2 enzymes do?
The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyze the formation of prostaglandins, thromboxane, and levuloglandins. The prostaglandins are autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors.
Where are COX-1 and 2 located?
COX-1 was found in blood vessels, interstitial cells, smooth muscle cells, platelets and mesothelial cells. In contrast, COX-2 was found predominantly in the parenchymal cells of many tissues, with few exceptions, for example the heart.
What is the COX-2 pathway?
COX pathway of arachidonic acid metabolism. COX-1 or COX-2 converts arachidonic acid to PGG2 and furthermore to PGH2 via COX and peroxidase activity. PGH2 is next metabolized to 5 major bioactive prostanoids—PGE2, PGI2, PGD2, PGF2, and TXA2—through their respective tissue-specific synthases.
What is the difference between prostaglandin and prostanoid?
Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction), and the prostacyclins (active in the resolution phase of inflammation).
What is the mechanism of action of COX-1 and COX-2 inhibitors within the human body?
There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining. NSAIDs block the COX enzymes and reduce production of prostaglandins.
What are COX-1 and COX-2 pathways?
Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs.
What is the difference between NSAIDs and COX-2 inhibitors?
COX-2-selective inhibitors are associated with a significant reduction in gastroduodenal damage compared with traditional NSAIDs. Proton pump inhibitors (PPI) are probably the best agents for healing and prevention of NSAID-induced ulcers.
What is the role of COX-2?
COX-2 is a key mediator of inflammatory pathways and its elevated expression has been found in several other human cancers as well. The relation between inflammation and cancer in general is well documented. Several recent studies on KSHV and EBV have pointed to the role of COX-2 in virus mediated tumorigenesis.
What is the COX-2 gene?
Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the PTGS2 gene....Prostaglandin-endoperoxide synthase 2.RNA expression patternBioGPSMore reference expression data1 more row
Is COX-2 a tumor suppressor?
The activity of COX-2-PGE2-EP signal pathway can suppress Dendritic cells (DCs), natural killer (NK), T cells, type-1 immunity excluding type-2 immunity which promote tumor immune evasion. COX-2 and the prostaglandin cascade play important roles in the “inflammogenesis of cancer”.
What does COX-1 do in the body?
COX-1 is known to be present in most of the tissues in your body. In the gastrointestinal tract, COX-1 maintains the normal lining of the stomach and intestines, protecting the stomach from the digestive juices. 4 The enzyme is also involved in kidney and platelet function.
What is the constitutively expressed form of COX?
The constitutively expressed form (normal for homeostasis) is referred to as COX-1, and the inducible form (in response to injury) is referred to as COX-2. COX-1 is found in platelets, GI mucosal cells, and renal tubule cells. COX-2 has been identified in fibroblasts, chondrocytes, endothelial cells, macrophages, and mesangial cells.
What is the role of COX-2 in cellular processes?
COX-2 is also involved in cellular processes including gene expression, differentiation , mitogenesis, apoptosis, bone modelling, wound healing and neoplasia. A new isoform, COX-3, has also been discovered in the brain.
What cells are exposed to COX-2?
COX-2 has been identified in fibroblasts, chondrocytes, endothelial cells, macrophages, and mesangial cells . COX-2 is induced by exposure to various cytokines, mitogens and endotoxin, and it is up-regulated at inflammation sites.
Is COX-1 a derivative?
It appears to be a derivative of COX-1, though its function has yet to be elucidated. The prostaglandins produced in the gastrointestinal tract and the kidney that maintain mucosal integrity in the upper GI tract and renal perfusion appear to be derived from COX-1.
Does COX-1 suppress prostaglandin synthesis?
It is suggested that COX-2 selective NSAIDs would suppress prostaglandin synthesis at sites of inflammation but would spare constitutive prostaglandin synthesis in the GI tract and kidney.
DEFINITION
Cyclooxygenase is an enzyme (EC 1.14.99.1) that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. It exists in two forms: COX -1 and COX -2
CHEMICAL STRUCTURE AND IMAGES
COX -1 has lower asparagine and higher proline, glycine and leucine (less proliferation and more protein synthesis??)
CELLULAR FUNCTIONS
The expression of both isoforms is regulated differently. The COX1 gene is expressed constitutively in almost all cells.
DIAGNOSTIC USE
A major mechanism for the regulation of prostaglandin synthesis occurs at the level of cyclooxygenase, also known as prostaglandin-endoperoxide synthase (PTGS; EC 1.14.99.1). The first rate-limiting step in the conversion of arachidonic acid to prostaglandins is catalyzed by PTGS.
What is the difference between COX 1 and COX 2?
In the gastrointestinal tract, COX-1 maintains the normal lining of the stomach and intestines, protecting the stomach from the digestive juices. 4 The enzyme is also involved in kidney and platelet function. COX-2, on the other hand, is primarily found at sites of inflammation. 5 Both COX-1 and COX-2 produce the prostaglandins ...
What is the purpose of COX-2?
The goal of these NSAIDs is to reduce pain and inflammation without losing the protection of COX-1 in the gastrointestinal tract, leading to fewer side effects .
What is the only COX-2 inhibitor?
These medications, known as COX-2 inhibitors, were Celebrex (celecoxib), Vioxx (rofecoxib), and Bextra (valdecoxib). 8 Of these, Celebrex is the only COX-2 inhibitor that remains on the market in the United States.
What is the effect of NSAIDs on COX?
Nonsteroidal anti-inflammatory drugs (NSAIDs) affect COX to reduce inflammation. 2 While they often do this successfully, some may negate some of the positive effects of COX in their efforts.
Does Cox 2 affect platelets?
COX-2 inhibitors target pain and inflammation with fewer gastrointestinal side effects. They also don't seem to affect platelets the way non-selective NSAIDs do, which means that COX-2 inhibitors may not increase bleeding risk as much as COX-1 inhibitors when used with blood thinners, like warfarin . As such, your doctor may prescribe ...
Can you take COX-2 instead of NSAID?
As such, your doctor may prescribe a COX -2 inhibitor instead of a traditional NSAID if you need both inflammation and pain relief, are on blood thinners, and/or have had ulcers or gastrointestinal bleeding or you're at risk for these issues. If you simply need pain relief, Tylenol (acetaminophen) may be considered instead.
Is COX bad for you?
1 But it turns out that COX isn't all bad; it's even necessary for normal cellular processes.
How does COX-2 work?
In intact cells, COX-2 utilizes a low concentration of arachidonic acid about equivalent to the concentration of arachidonic acid released endogenously. This means the production of prostaglandins via COX-2 is regulated by the activation of phospholipases and the expression of the COX-2 gene. Many cytokines and growth factors affect the phospholipases and COX-2, and glucocorticoids inhibit both phospholipase activity and the induction of COX-2. In contrast, COX-1 functions only at relatively high concentrations of arachidonic acid, corresponding to those observed when arachidonic acid is added exogenously or during platelet aggregation or cell injury or acute inflammation.
What is the role of COX-1 in tumorigenesis?
In tumorigenesis the role of COX-1 is distinct from that of COX-2. COX-1 is expressed in vascular endothelial cells and contributes to angiogenesis , which is an endothelial cell function and is involved in growth of tumors, endometrial growth , wound healing and inflammation.
Is COX1 a tumor?
COX has been implicated in the development of malignant tumors by epidemiological studies, work with gene-disrupted mice and COX overexpression and pharmacological studies. In tumorigenesis the role of COX-1 is distinct from that of COX-2. COX-1 is expressed in vascular endothelial cells and contributes to angiogenesis, which is an endothelial cell function and is involved in growth of tumors, endometrial growth, wound healing and inflammation. The origin of the neovasculum is thought to be microvessel endothelial cells and circulating endothelial cell precursors [67]. Human umbilical endothelial cells or aortic endothelial cells are commonly used in vitro as an angiogenesis model. In this system, an anti-sense oligonucleotide to COX-1 suppresses tube formation induced by colon cancer cells overexpressing COX-2 [68]. However, in our laboratory NSAIDs treatment of endothelial cells cultured between collagen gels did not cause inhibition of tube formation induced by high concentration of vascular endothelial growth factor (VEGF) (unpublished results). One possibility to explain this apparent discrepancy is that the contribution of COX-1 to angiogenesis may be dependent on the stimulator of angiogenesis.
EXPERIMENTAL PROCEDURES
Arachidonic acid was purchased from Nu-Chek-Prep Inc. (Elysian, MN); CHAPS, hemin chloride, TMPD, Tris, and heme (bovine hemin chloride) were purchased from Sigma; all other reagents were purchased from Fisher Scientific. NS-398 ( N - (2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide) was provided by Dr.
RESULTS
COX-1 and −2 are 63% identical and 77% similar at the amino acid level. A cursory look at the sequence alignment of human COX-1 and COX-2 reveals that most of the major differences are in the N-terminal and C-terminal regions.
DISCUSSION
With the identification of a second COX isoform, numerous groups have embarked on efforts to identify selective inhibitors of COX-2. Prior to their discovery, the ability to identify selective inhibitors of COX-2 was not obvious as the enzymes utilize the same substrate and have a high degree of sequence homology.
What is the difference between Cox 1 and Cox 2?
An important difference between COX enzymes is in their expression and induction patterns (Table 1) [ 25, 26 ]. Tissue localization studies under basal physiological conditions have found expression of COX-1 in virtually all tissues, whereas COX-2 appears to be restricted to the kidney, brain, testicles and tracheal epithelial cells [ 8, 9, 17, 25, 27 – 29 ]. Although COX-1 predominates in the gut [ 25 ], a certain amount of COX-2 has also been detected in the surface mucous cells of rats [ 30] and in human small intestine [ 27 ].
How many folds is COX-2 upregulated?
COX-2 can be upregulated 20-fold in macrophages, monocytes, synoviocytes, chondrocytes, fibroblasts and endothelial cells by various stimuli during the inflammatory process [ 13, 17, 22, 31, 32 ]. In contrast, COX-1 activity is unaffected or increased only marginally (2- to 4-fold) [ 33 ].
Does NSAID inhibit COX isoforms?
The degree to which an NSAID inhibits the COX isoforms in vitro depends on the experimental assay used to assess enzyme inhibition. Variables such as incubation time with the drug, the species from which the isoform has been isolated or use of exogenous vs endogenous substrate can influence the IC 50 values and, therefore, affect the COX-2/COX-1 ratio.
Does Celecoxib inhibit COX-2?
In a purified recombinant enzyme in vitro assay system, celecoxib inhibits COX-2 [ 64 ]. Celecoxib (Celebrex ™ , G. D. Searle & Co.) has been demonstrated to have no effect on whole-blood thromboxane B 2 production—a measure of COX-1 activity [ 65 ]. Six healthy men received celecoxib 400 mg twice daily for 5 days and as a single dose on the sixth day. Whole-blood thromboxane B 2 levels were determined 90 min before, and 2, 4 and 12 h after the last dose on day 6. Furthermore, as discussed below, celecoxib, at or below these doses, has been shown to be effective in OA and in dental pain studies. These data demonstrate that celecoxib also fulfils the definition of COX-2 specificity in man.
Does whole blood assay exclude COX-1 inhibition?
The whole-blood assay for COX-1 inhibition, which assesses an agent's action on COX-1 in platelets, does not absolutely exclude inhibition of COX-1 at other sites such as the gastric mucosa. It is important, therefore, that COX-1 inhibition in other tissues throughout the body is assessed.
Is Cox-2 specific?
The definition states that if a drug inhibits COX-2, but not COX-1, across the therapeutic dose range, using the whole-blood assays, then it is COX-2 specific. This definition of COX-2 specificity has the advantage that it is independent of the variation resulting from differences between assays for COX-1 and COX-2.
Do NSAIDs inhibit COX-1?
Following the identification of COX-1 and COX-2, the degree to which NSAIDs differentially inhibit the two isoforms has been assessed. Relative inhibition of COX-1 and COX-2 has been estimated through the development of a wide variety of in vitro assay systems.
How are COX1 and COX2 similar?
COX-1 and −2 are 63% identical and 77% similar at the amino acid level. A cursory look at the sequence alignment of human COX-1 and COX-2 reveals that most of the major differences are in the N-terminal and C-terminal regions. The catalytic domain (117–587) is highly conserved, with the major residues known to be involved in catalysis or heme binding; Arg-120, His-206, Tyr-385, His-386, and His-388 all conserved, along with the residue which is acetylated by aspirin (Ser-530). Differences that could be responsible for selectivity are most likely found in the cyclooxygenase active site rather than the peroxidase site, due to the fact that the known selective inhibitors, as do most common NSAIDs, inhibit the cyclooxygenase activity and not the peroxidase activity.
Is Cox-2 selective inhibitor?
With the identification of a second COX isoform, numerous groups have embarked on efforts to identify selective inhibitors of COX-2. Prior to their discovery, the ability to identify selective inhibitors of COX-2 was not obvious as the enzymes utilize the same substrate and have a high degree of sequence homology. Nonetheless, we and others have reported the identification of selective inhibitors of COX-2 ( 16, 23 ). The mechanism of inhibition of COX-2 has been described as “time-dependent,” involving a tight binding component, while these compounds are reversible inhibitors of COX-1. ( 17 ). This time-dependent component is the apparent basis for selectivity of this new class of COX-2 inhibitors, since these compounds are reversible inhibitors of COX-1. To further understand the molecular basis of this differential inhibition, a series of mutants was evaluated. We observed that a single amino acid change in COX-2 confers a COX-1 inhibitory profile for these COX-2 selective inhibitors. Specifically, the data suggest that the mechanism for selectivity is intimately associated with the removal of a single methyl group at position 523. Therefore, the time-dependent step could possibly be inhibited by the presence of an additional methyl group in the substrate channel.