Thromboxane synthase

TXA2 is produced by activated platelets via the sequential conversion of arachidonic acid by phospholipase A2, cyclooxygenase-1 (COX-1), and thromboxane synthase. Similar to ADP, TXA2 acts as a... 

Tienilic acid- and dihydralazine-induced hepatitis are associated with antibodies against Cyp 2C9 [53] and Cyp 1A2 [54, 55], respectively. These are also the same cytochrome P450s that are responsible for the formation of reactive metabolites of these two drags. Anticonvulsant hepatotoxicity is associated with antibodies against rodent Cyp 3 A and related human enzymes such as thromboxane synthase [56, 57], It is interesting to note that cytochromes P450 are often the target of autoantibodies in idiopathic autoimmune hepatitis [58],... 

Chevalier D, Lo-Guidice JM, Sergent E, Allorge D, Debuysere H, et al. 2001. Identification of genetic variants in the human thromboxane synthase gene (CYPSAl). Mutat Res 432 61-67. 

V. Ulhich, H. Graf (1984). Prostacychn and thromboxane synthase as P-450 enzymes. Trends Pharmacol. Sci. 5 352-355. 

Thromboxane synthase, present in blood platelets (thrombocytes), converts PGH2 to thromboxane A2, from which other thromboxanes are derived (Fig. 21-15a). Thromboxanes induce constriction of blood vessels and platelet aggregation, early steps in blood clotting. Low doses of aspirin, taken regularly, reduce the probability of heart attacks and strokes by reducing thromboxane production. ... 

In blood platelets and in some other tissues PGG is also transformed to another series of compounds, the thromboxanes,270 which were identified in 1975. Labile hemiacetals, the thromboxanes A (TXA, Fig. 21-7), are derived by rearrangement of PGH (step g). Thromboxane synthase,271-273 which catalyzes the reaction, has characteristics of a cytochrome P450. Cytochromes P450 are known to react with peroxides as well as with 02, and the endoperoxide of PGH may be opened by the synthase prior to rearrangement to TXA.273 Thromboxane A2 is so unstable that its half-life at 37°C in water is 36 s. It is spontaneously converted to TXB2 (Fig. 21-7), which contains an -OH group at C-15. The thromboxanes B are much more stable than TXA but are not very active physiologically. 

Fig. (6). Vasoconstrictor mechanism of myricetin. PLA2 phospholipase A2 PL phospholipids AA arachidonic acid COX cyclooxygenase PGG2 prostaglandin G2 PGES prostaglandin endoperoxide synthase PGH2 prostaglandin Hi TXS Thromboxane synthase TXA2 Thromboxane A2 Tp Thromboxane receptor PKC protein kinase C.

Ullrich V and Brugger R (1994) Prostacyclin and thromboxane synthase new aspects of hemethiolate catalysis. Angew Chem Int Ed Engl 33, 1911-1919. 

Morimitsu et al. (2000) have shown that after incubation with MS-ITC (5 or 10 min), the treated platelets were washed two times with phosphate-buffered saline, and MS-ITC potently inhibited platelet aggregation induced by thrombin. Then, MS-ITC could not show any effects on arachidonic acid cascade (phospholipase A prostaglandin synthase, and thromboxane synthase) in human platelets. 

The development of selective thromboxane synthase inhibitors and TXA2 receptor antagonists has required considerable effort. The resulting compounds, eg, sulotroban, have been useful for characterizing TXA2-related effects in vitro and in vivo. They are being tested in the treatment of thromboembolism, pulmonary hypertension, and preeclampsia-eclampsia. 

The mildness of this defect is supported by the fact that very modest hemostatic defects are noted in patients with diseases involving deficiencies of platelet COX and thromboxane synthase—eg, these patients have no history of increased or decreased bleeding. Blockade of either of these two enzymes inhibits secondary aggregation of platelets induced by ADP, by low concentrations of thrombin and collagen, or by epinephrine. Thus, these platelet enzymes are not necessary for platelet function but may amplify an aggregating stimulus. 

COX), and thromboxane synthase are restricted to the intracellular dense tubular and granules membranes. 

Inhibitors of thromboxane synthase are an example of heterogeneous-relaxed SARs. The ligand spectrum includes diverse and highly potent inhibitors, similar to factor Xa, but also pairs of structurally similar inhibitors having very different potency (Figure 4.7c). In this case, the coexistence of continuous... 

Numerous TP receptor antagonists have been synthesized with the intent that they would be usefiil agents to block the adverse effects of TXAj in human diseases (See 94,222 for reviews). Some of these agents arc specific TP receptor antagonists, while others have combined TP receptor antagonist and thromboxane synthase inhibitory properties. 

Hoet B, Amout J, Van Geet C, Deckmyn H, Verha e R, Vermylen J. Ridogrd, a cnnbined thromboxane synthase inhibitor and receptor blocker, decreases elevated plasma p-thrombc>globulin levds in patients with documented peripheral arterial disease. Thromb Haemost 1990 64 87-90... 

Gresele P, Dedomyn H, Amout J, N nci GG, V rmyl n J. Characterization of N,N -t>is(3 pioolyl)-4-methoxy-isophthalamide (piootamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. HircmibHaemost 1989 61 479-84... 

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