Prostaglandins synthetase

Aminophenol is a selective nephrotoxic agent and intermpts proximal tubular function (121,122). Disagreement exists concerning the nephrotoxity of the other isomers although they are not as potent as 4-aminophenol (123,124). Respiration, oxidative phosphorylation, and ATPase activity are inhibited in rat kidney mitochondria (125). The aminophenols and their derivatives are inhibitors of 5-Hpoxygenase (126) and prostaglandin synthetase... 

Paradoxically, the thia2ides are efficacious, especially if combined with a prostaglandin synthetase inhibitor such as indomethacin or aspirin, in the treatment of nephrogenic diabetes insidipus, in which the patient s renal tubules fail to reabsorb water despite the excessive production of ADH (28). Thia2ides can decrease the urine volume up to 50% in these patients. 

Hawkey, C.J. and Truelove, S.C. (1983). Inhibition of prostaglandin synthetase in human rectal mucosa. Gut 24, 213-217. 

TABLE 33-1 Characteristics of cyclooxygenases or prostaglandin synthetases (IUPAC IUB EC 1.14.99.1)... 

Pugh WJ, Sambo K. (1988). Prostaglandin synthetase inhibitors in feverfew. J Pharm Pharmacol. 40(10) 743-45. 

As a prostaglandin synthetase inhibitor, diflunisal exhibits analgesic, fever-reducing, and anti-inflammatory action. It is used for long- and short-lasting symptomatic relief of low to moderate pain in osteoarthritis and rheumatoid arthritis.Synonyms for this drug are dolobid, adomal, noladol, and others. 

This series of anti-inflammatory, analgesic, and fever-reducing compounds (ibuprofen, naproxene, ketoprofen, fenprofen) can be equally identified as both propionic acid derivatives as well as phenylpropionic acid derivatives. The mechanism of their action is not conclusively known however, it has been suggested that it is also connected with the suppression of prostaglandin synthetase activity. 

Pharmacology The site and mechanism of the analgesic effect is unclear. APAP reduces fever by a direct action on the hypothalamic heat-regulating centers, which increases dissipation of body heat (via vasodilatation and sweating). APAP is almost as potent as aspirin in inhibiting prostaglandin synthetase in the CNS, but its peripheral inhibition of prostaglandin synthesis is minimal. 

Pharmacology Salicylates have analgesic, antipyretic, anti-inflammatory, and antirheumatic effects. Salicylates lower elevated body temperature through vasodilation of peripheral vessels, thus enhancing dissipation of excess heat. The anti-inflammatory and analgesic activity may be mediated through inhibition of the prostaglandin synthetase enzyme complex. 

III.a.4.3. Changes in renal blood flow. Blood flow through the kidney is partially controlled by the production of renal vasodilatory prostaglandins. If the synthesis of these prostaglandins is inhibited (e.g. by indomethacin), the renal excretion of lithium is reduced with a subsequent rise in serum levels. The mechanism underlying this interaction is not entirely clear, as serum lithium levels are unaffected by some potent prostaglandin synthetase inhibitors (e.g. aspirin). If an NSAID is prescribed for a patient taking lithium the serum levels should be closely monitored. 

The peripheral component of their analgesic action is due to the inhibition of prostaglandin synthetase and thereby inhibiting the synthesis of prostaglandins (PGs) which sensitise the pain receptors to mechanical and chemical stimuli. Aspirin inhibits prostaglandin synthesis and blocks the sensitization of pain mechanism. 

Apazone is an analgesic (pain reliever) not currently available in the United States. It is absorbed well through the G.l. tract and binds extensively to plasma proteins thereby extending its half-life (20-24 hours). Its mode of action is to inhibit prostaglandin synthetase. This, in turn, affects the pain centers and decreases the inflammatory response. 

For foreign compounds, the majority of oxidation reactions are catalyzed by monooxygenase enzymes, which are part of the mixed function oxidase (MFO) system and are found in the SER (and also known as microsomal enzymes). Other enzymes involved in the oxidation of xenobiotics are found in other organelles such as the mitochondria and the cytosol. Thus, amine oxidases located in the mitochondria, xanthine oxidase, alcohol dehydrogenase in the cytosol, the prostaglandin synthetase system, and various other peroxidases may all be involved in the oxidation of foreign compounds. 

Figure 4.37 Co-oxidation of a drug by the prostaglandin synthetase enzyme system.

Various enzymes can produce reactive intermediates by metabolism, especially cytochrome P-450, but also peroxidases, FMO, prostaglandin synthetase, MAO. 

Degen GH, Vogel C, Abel J. Prostaglandin synthetases. In Ioannides C, ed. Enzyme Systems that Metabolise Drugs and Other Xenobiotics. Chichester John Wiley and Sons, 2002 188-229. 

Metabolic activation. Although the kidney does not contain as much cytochromes P-450 as the liver, there is sufficient activity to be responsible for metabolic activation, and other oxidative enzymes such as those of the prostaglandin synthetase system are also present. Such metabolic activation may underlie the renal toxicity of chloroform and paracetamol (see chap. 7). Other enzymes such as C-S lyase and GSH transferase may also be involved in the activation of compounds such as hexachlorobutadiene (see chap. 7). In some cases, hepatic metabolism may be involved followed by transport to the kidney and subsequent toxicity. 

It should also be mentioned that prostaglandin synthetase can activate paracetamol (Fig. 7.20) to reactive metabolites. Although probably not the primary route of activation in the liver, it has been suggested that this could be important in the kidney (which can also be damaged in paracetamol overdose). 

Figure 7.20 Activation of paracetamol by prostaglandin synthetase system to reactive radical intermediates.

Two pyrrole derivatives bearing a significant structural resemblence to indomethacin are tolmetin (10) and chlopirac (11) (78MI30600, 76MI30600). Tolmetin has received clinical comparison with aspirin and with indomethacin in rheumatoid arthritis and generally was found to have comparable effectiveness, but a somewhat diminished tendency to cause lesions in the digestive tract. Like indomethacin, it seems to function as a prostaglandin synthetase inhibitor. 

Moncada S, Ferreira SH, Vane JR. Sensitization of pain receptors of dog knee joint by prostaglandins. In Robinson HJ, Vane JR, editors. Prostaglandin Synthetase Inhibitors. New York Raven Press, 1974 189. 

Phase I reactions include microsomal monooxygenations, cytosolic and mitochondrial oxidations, co-oxidations in the prostaglandin synthetase reaction, reductions, hydrolyses, and epoxide hydration. All of these reactions, with the exception of reductions, introduce polar groups to the molecule that, in most cases, can be conjugated during phase II metabolism. The major phase I reactions are summarized in Table 7.1. 

Oxidation Cytochrome P450s Prostaglandin synthetase Flavin-containing monooxygenases Alcohol and aldehyde dehydrogenases... 

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