Thromboxane A, TXA

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. 

Phospholipase C (both p and y) catalyzes the hydrolysis of Phosphatidyl inositol bisphosphate (PIPj) leading to the generation of diacylglycerol (DAG) and inositol trisphosphate (IP,). In platelets, thrombin and thromboxane-A, (TxA,) stimulate PLC-p. PLC-P has three isotypes. It is known that PLC-pi and PLC-P3 are activated by G-protein... 

Thromboxane synthetase has been solubilized and partially purified from human >53 gnd bovine blood platelets and from sheep and bovine lung. The enzyme activity also has been studied in platelet membranes by several workers.39-63 Recent studies indicate that the same enzyme catalyses the formation of TXA2 and hydroxyheptadecatrienoic acid (HHT) in a bimolecular reaction and that the formation of both products is inhibited in parallel.34,60,61 These studies also show that the formation of HHT does not involve TXA2 as an Intermediate and that TXA2 is converted exclusively into TXB2. PGH, the endoperoxlde from eicosapentaenoic acid (C2O 5 3,8,11,14,17) is converted into thromboxane A (TXA ) by platele... 

In blood platelets and in some other tissues PCC is also transformed to another series of compounds, the thromboxanes, which were identified in 1975. Labile hemiacefals, the thromboxanes A (TXA, Fig. 21-... 

INHIBITION OF PROSTAGLANDIN BIOSYNTHESIS BY NSAIDS The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also known as COX. This enzyme converts arachidonic acid (AA) to the unstable intermediates PGGj and PGH and leads to the production of thromboxane A (TXA ) and a variety of prostaglandins (see Chapter 25). 

Figure 12.11. StractuiES of two thromboxane A receptor blockers (a), and of BM 573, a combined antagonist of both TXA receptor and TXA synthase (b). BM 573 was derived from the diuretic torasemide.

Platelet adenylate cyclase formation in turn is stimulated by prostacyclin (from the endothelium, also called PGy and inhibited by thromboxane-A (from within platelets, also called TXA ). 

Thromboxanes (TX). Cyclic eicosanoids occurring in all body tissues. The compounds are classified into a TXA- (bicyclic structure with an oxetane ring) and a 7XS- eries (cyclic structure in which the oxetane ring has been hydrolytically cleaved) an index number indicates the number of C,C-double bonds in the molecule. T. are formed in the cyclooxygenase biosynthesis pathway from arachidonic acid and other multiply unsaturated fatty acids, the first biosynthetic steps on the way to the T. and to the prostaglandins are identical (see figure). The multiply unsaturated fatty acids are first released from phosphatidylcholines and other phospholipids of the cell membrane by phospholipase A,. 

Some compounds with thromboxane-like structure have been screened for agonist activity on thromboxane sensitive systems. Carbocyclic TXAj [155,245,246] behaved as a potent TXA2 agonist on the vasculature (isolated cat coronary artery) but rather as an antagonist on arachidonic acid induced platelet aggregation. The TXA, analogue, 9a-homo-(l l,12)-deoxa-(l l,12)-methylene thromboxane A, showed weak TXA 2-like properties with respect to vasoconstriction but had no effect on platelet aggregation [247]. 

Thromboxane A synthase (TXAS) catalyses the conversion of PGH to TXAj, a potent mediator of coagulation, vasoconstriction and broncho-constriction. TXA breaks down non-enzymatically into the stable but inactive TXBj (Figure 3). Like PGIS, TXAS is a hemoprotein and member of the cytochrome P450 superfamily. It is expressed in a variety of tissues, including platelets, where its activity is clearly coupled to COX-1 (Miyata et al, 1994 Ullrich et al, 2001). 

Fuse I, Hattori A, Mito M, Higuchi W, Yahata K, Shibata A, Aizawa Y. Pathogenetic analysis of five cases with a platelet disorder ehvacterized by the absence of thromboxane Aj (TXA2)-induced platelet aggregation in spite of normal TXA binding activity. Thromb Haemost 1996 76 1080-5... 

Thromboxane A2 also causes contraction of the smooth muscles in the artery, thus minimizing blood loss in the artery in the vicinity of the injury. As mentioned earlier, TXA binds to a "contractile receptor."... 

PGH2 may be converted to the thromboxane TXA2, a reaction catalyzed by TXA synthase (see Fig. 35.8). This enzyme is present in high concentration in platelets. In the vascnlar endothelium, however, PGH2 is converted to the prostaglandin PGI2... 

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