Cyclooxygenase activity/inhibition

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

Platelet Inhibition Ginger extract has been found to inhibit platelet aggregation induced by arachidonic acid, epinephrine, ADP, and collagen (Srivastava 1984). The extract s ability to inhibit cyclooxygenase activity and thromboxane levels correlated well with inhibition of platelet aggregation (Srivastava 1984 Mustafa et al. 1993). The type of preparation used also affects platelet inhibition, because roasted and charcoal of ginger were effective, while ether extracts of raw and dried ginger were not (Wu et al. 1993). 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

Pharmacology Nonsteroidal anti-inflammatory drugs have analgesic, antipyretic, and anti-inflammatory activities. Major mechanism is believed to be inhibition of cyclooxygenase activity and prostaglandin synthesis. 

Broussochalcone A (32) Antioxidant activity (inhibition of lipid peroxidation) Inhibition of cyclooxygenase Inhibition of nitric oxide production Inhibition of respiratory burst in neutrophils Platelet aggregation inhibitory activity1 [42] [431 [42] [44] [431... 

Broussoflavonol F (45) Antioxidant activity (inhibition of lipid peroxidation) Antiproliferative activity Inhibition of aromata eb Inhibition of cyclooxygenase Platelet aggregation inhibitory activity11 [45] [45] [41] [43] [43]... 

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

Tylenol inhibits the peroxidase activity and aspirin inhibits the cyclooxygenase activity. 22.46 because dead heart muscles spill their enzyme contents into the serum 22.48 They are both basic amino acids. 

Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. 2004. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin Dl, and abrogation of tumor cell proliferation. Oncogene 23 9247-9258. 

A useful insight into the subtle differences between the catalytic sites of the two enzymes was provided by the observations that while the cyclooxygenase activities of both were inhibited by aspirin, aspirin-acetylated Cox-2 has an increased 15-oxygenase activity, which can be inhibited by some Cox inhibitors (Mancini et al., 1994 Lecomte et al., 1994). Aspirin is known to acetylate Ser-530 of Cox-1 and Ser-516 of Cox-2. Apparently, in the acetylated Cox-2 catalytic site there is still room for arachidonate to enter in an extended conformation, which permits catalysis of 15-hydroperoxyeicosatetraenoic acid formation but not of PGG2 formation. This led to the conclusion that the catalytic site of Cox-2 must be slightly larger than that of Cox-1, a conclusion later... 

The drug acetylsalicylic acid (aspirin) irreversibly inhibits the cyclooxygenase activity, while ibuprofen inhibits the reductase activity. Both drugs treat inflammation, pain, and fever because they inhibit prostaglandin synthesis. Prostaglandins are very unstable, so they tend to act locally (otherwise a sprained ankle would cause pain throughout the body). 

Aspirin (acetylsalicyclic add) causes irreversible acetylation of cyclooxygenase and inhibits the formation of PGs. Because mammalian platelets do not have a nucleus and the ability to carry out transcription and translation, they do not have the ability to resynthesize cyclooxygenase. New platelets must be formed, which takes several days. Other nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin, ibuprofen, and phenylbutazone, also inhibit cylooxygenase by competing with the substrate AA at the active site. 

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