Thromboxanes and Prostacyclins

Figure 11.16 Structure of prostanoate, and three eicosanoids. Structurally, prostaglandins, thromboxanes and prostacyclins may be regarded as derivates of prostanoate, that is, they contain 20 carbon atoms and a saturated five membered ring (cyclopentane).

Cyclooxygenase converts arachidonic acid first to prostaglandin G (PGG) and then to PGH prior to formation of prostaglandins, thromboxanes and prostacyclins. The structures of the intermediates and some of the end-products of these conversions are provided in Figure 11.28. 

The prostaglandins, thromboxane, and prostacyclin, collectively termed the prostanoids, are generated from PGH2 through the... 

Cyclooxygenase pathway All eicosanoids with ring structures, that is, the prostaglandins, thromboxanes, and prostacyclins, are synthesized via the cyclooxygenase pathway. Two cyclooxygenases have been identified COX-1 and COX-2. The former is ubiquitous and constitutive, whereas the latter is induced in response to inflammatory stimuli. The products of these and subsequent reactions in this pathway are summarized in Figure 39.3. 

The eicosanoids are a group of biologically active compounds containing 20 carbon atoms derived from arachidonic acid. The prostaglandins (Section 19.6) and the leukotrienes (Section 9.16) are two types of eicosanoids. Two others are the thromboxanes and prostacyclins. 

Two pathways of metabolism are available for arachidonic acid. The first is the cyclooxygenase pathway, which leads to the formation of prostaglandins, thromboxanes, and prostacyclin. The second is the lipoxygenase pathway. Lipoxygenase catalyzes the first step in the conversion of arachidonic acid to a number of noncyclized metabolites. These metabolites include 5-hydroperoxyei-cosatetraenoic acid (HPETE) and the leukotrienes (Figure 9.101). 

Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, Jakobsson PJ, Mamett LJ (2002a) Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides. J Biol Chem 277 44877 4885... 

Eisenmann CJ, Miller RK. 1995. The effect of selenium compounds (selenite, selenate, ebselen) on the production of thromboxane and prostacyclin by the human term placenta in vitro. Toxicol Appl Pharmacol 135 18-24. 

Guo et al. (1990) working with an in vivo rabbit model showed that pre- or posttreatment with indomethacin, an inhibitor of thromboxane and prostacyclin production but not of leukotriene production, partially blocked phosgene-induced pulmonary oedema. The leukotriene receptor blockers FPL 55712 and LY 171883 dramatically reduced the oedema when given post-exposure to phosgene. 

Torras J, Valles J, Sanchez J, Sabate I, Seron D, Carrera M, Castelao AM, Herrero I, Puig-Parellada P, Alsina J, Grino JM. Prevention of experimental cyclosporine nephrotoxicity by dietary supplementation with LSI 90202, a lysine salt of eicosapentaenoic acid. Role of thromboxane and prostacyclin in renal tissue. Nephron 1994 67 66-72. 

Bruggeman LA, Pellicoro JA, Horigan EA, Klotman PA. Thromboxane and prostacyclin differentialy regulate murine extracellular matrix gene expression. Kidney Int 1993 43 1219-1225. 

Both of these effects are due to the inhibition of an enzyme, cyclo-oxygenase (COX). This enzyme normally converts arachidonic acid to prostaglandins, thromboxanes and prostacyclin. (See Figure 7.1.)... 

Honn KV, Meyer J. Thromboxanes and prostacyclin positive and negative modulators of tumor growth. Biochem Biophys Res Commun. 102 (1981) 1122-1129. 

In addition to serving as a precursor for the synthesis of prostaglandins, PGH2 is a precursor for the synthesis of thromboxanes and prostacyclins. Thromboxanes constrict blood vessels and stimulate the aggregation of platelets, the first step in blood clotting. Prostacyclins have the opposite effect, dilating blood vessels and inhibiting... 

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