COX enzyme

Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body s synthesis of prostaglandins (Sections 7.11 and 27.4). There are two forms of the enzyme, COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only tire response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. 

Most NSAIDs (e.g., ibuprofen, naproxen, and others) inhibit both COX-1 and COX-2 isoforms. That is, they are nonselective inhibitors of the COX enzyme system. Whereas inhibition of COX-2 is responsible for beneficial effects, inhibition of COX-1 is responsible for the most common and important adverse effects of NSAIDs. COX-2-selective inhibitors have been produced and marketed in attempts to preserve the beneficial effects of COX-2 inhibition while avoiding the deleterious effects associated with inhibition of the COX-1 enzyme. This approach has not been entirely successful, as discussed below. 

Recently, it has been shown that inhalation of MWNTs caused suppression of the systemic immunity without resulting in significant lung inflammation or tissue damage [82,83]. Inhaled MWNTs in fact modified the functionality of spleen cells in exposed mice [82]. Notably, the activity of cyclooxygenase (COX) enzymes in spleen was affected as a response to a cytokine (TGF(5) released from the lungs. This cytokine activated the COX pathway in the spleen, triggering T-cell dysfunction and systemic immunosuppression [83]. 

A variety of biochemical and molecular mechanisms have been described to explain how PUFAs can modulate immune cell fate and function. The primary mechanism of action of dietary n-3 PUFAs involves the replacement of AA in the lipid membrane of the cells with either EPA or DHA. This, in effect, competitively inhibits the oxygenation of AA by the COX enzymes. For example, the EPA-induced suppression in the production of AA-derived eicosanoids is followed by a subsequent increase in the production of those from EPA. Generally, the EPA-derived eicosanoids are considered to be much less potent than those from AA, thus explaining, at least partially, the anti-inflammatory effects of PUFAs. A similar mechanism of action can be demonstrated for DHA, either directly or by retroconversion to EPA. 

In the early 1990s two isoforms of the COX enzyme were found COX-1 and COX-2, with about 60% homology between them (there is actually a COX-3, but it is a variant of COX-1 there are differences in the two active sites between COX-1 and COX-2, with the latter possessing an additional hydrophilic pocket). 

Aspirin is a rather simple molecule that has important analgesic, anti-inflammatory, and antipyretic properties. It is known how aspirin works it is an irreversible inhibitor of COX. In fact, there are three human COX enzymes more about this follows below. 

Compare this situation with that for normal and sickle cell hemoglobins. The two COX enzymes are both fully functional and differ by a single conservative amino acid replacement. In contrast, normal hemoglobin is fully functional but sickle cell hemoglobin is not and these differ by a single nonconservative amino acid replacement (see chapter 11). 

As shown in a paper by Conderoy et al. (2008), there is an increasing amount of evidence that-suggests an association between cancer and the cyclooxygenase (COX) enzyme (5) hence, the COX-expressing cell line fiT-29 was studied in this present work. 

The COX enzyme exists in at least two isoforms. COX-1 is a constitutive or housekeeping isoform that is responsible for the basal production of prostaglandins, prostacyclins, and thromboxanes. COX-2 is inducible by cytokines and other inflammatory stimuli and is believed to predominate during chronic inflammation. The final product of the COX pathway is tissue specific. For example, platelets produce thromboxane A2 (TXA2) vascular endothelial cells produce prostacyclin (PGI2) mast cells produce prostaglandin Dj (PGD2) ... 

Conversely, to the (5)-enantiomer, it does not inhibit COX enzymes, but it is an apoptosis inductor. It is also in phase III evaluation for treatment of Alzheimer dementia vide infra) Celebrex, another NS AID drug, is also being evaluated for the treatment of several cancers. 

The mode of action of these compounds, which are under investigation, is via an antioxidative mechanism. Since COX enzyme catalysis involves radical intermediates, a radical scavenging moiety such as a di-fenf-butylphenol interferes with the cyclooxygenase reaction. Linkage of phenolic substructure with a thiazolone, oxazolone, thiadiazole or oxadiazole derivative produces non-... 

The cyclooxygenase (COX) enzyme is known to exist as two distinct isoforms. COX-1 is a constitutively expressed housekeeping enzyme found in nearly all tissues and mediates physiological responses. COX-2 is an inducible form expressed primarily by cells involved in the inflammatory response. Several tissues low in CYP expression are rich in COX, which is believed to have significance in the carcinogenic effects of aromatic amines in these organs. 

One of the most interesting things about human COX enzymes is that there is more than one of them—definitely two, and probably at least three. This is important to our understanding of the therapeutic effects of ibuprofen, aspirin, and acetaminophen. It had long been suspected that there was more than one COX enzyme, but it was not until 1991 that evidence for the existence of two forms, COX-1 and COX-2, materialized. It was then recognized that COX-1 is present at near constant levels in the body under all conditions (that is, it is a constitutive enzyme), whereas the levels of COX-2 could increase in response to inflammatory conditions (i.e., it is an inducible enzyme). This led to the idea that the side effects of ibuprofen and aspirin (including stomach ulcers) probably arose from inhibition of the constitutive COX-1 enzyme, whereas the therapeutic benefits arose from inhibition of the inducible COX-2 enzyme. 

Ibuprofen and aspirin both inhibit COX-1 and COX-2, but they do it in different ways. Ibuprofen binds noncovalently to a COX enzyme and thus competes with the enzyme s natural substrate. (This is referred to as reversible... 

The prostaglandins produced by the COX enzyme have uses in the body in addition to their role in pain response, including maintaining the health of the stomach lining, regulating blood flow to the kidneys, and enabling specialized blood cells called platelets to initiate the process of blood clotting. Because the COX enzyme is responsible for all of these other functions, there are some potentially harmful side effects of NSAIDs, as will be discussed below. 

Figure 2.1 This figure illustrates the main chemical messengers involved in producing pain signals. Injured tissue cells release lipids that are converted into prostaglandins by the COX enzyme, which then activate nociceptors on sensory nerve fibers. Immune cells at the site of damage can release histamine, which also activates nociceptors. Nerve endings can also release peptides such as substance P, which alter the activity of immune cells or make blood vessels dilate and cause swelling.

---