Thromboxanes biosynthesis

Poland, platelet-inhibiting effects have been observed with bisarylpyridazines of type (70, R = H, Me, Br, Cl R2 = H, Me) [270]. In France, the arylidenedi-hydropyridazines (71) and (72) have been investigated [271, 272]. They have been found to inhibit thromboxane biosynthesis. 

Malonaldehyde is found in human and animal tissue as an end-product of lipid peroxidation. It is also a side-product of prostaglandin and thromboxane biosynthesis. Malonaldehyde is present in blood platelets and in serum (lARC, 1985). 

As discussed previously, aspirin inhibits platelet-induced thrombus formation through its ability to inhibit thromboxane biosynthesis. Aspirin has therefore been used to help prevent the onset or recurrence of heart attacks in some individuals by inhibiting thrombus formation in the coronary arteries.97,109 Similarly, daily aspirin use may help prevent transient ischemic attacks and stroke by preventing cerebral infarction in certain patients.97,109 The role of aspirin in treating coagulation disorders is discussed in more detail in Chapter 25... 

Eikelboom JW Hirsh J, Weitz Jl, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002 105 1650-1655. 

Fitzgerald DJ, Wright F, FitzGerald GA (1989) Increased thromboxane biosynthesis during coronary thrombolysis evidence that platelet activation and thromboxane A2 modulate the response to tissue-type plasminogen activator in vivo. Circ Res 65 83-94... 

Anti-inflammatory Cyclooxygenase inhibitor, inhibits prostaglandin, prostacyclin, thromboxane biosynthesis Anti-inflammatory Cyclooxygenase inhibitor, inhibits prostaglandin, prostacyclin, thromboxane biosynthesis... 

Fitzgerdd DJ, Ma o G, Catdla F, Eniman SS, FitzGerald GA. Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platdets. Am J Obstet Gynecol 1987 157 325-30... 

Mobely A, and Tai HH. (1983). Synergistic stimulation of thromboxane biosynthesis by calcium ionophote and phorbol ester or thrMnbin in human platelets. Biochem. Biopliys. Res. Conmuin. 130,717-723. 

Averna M, Barbagallo CM, Ganci A, Giammarresi C, Cefalu AB, Sparacino V, Caputo F, Basil S, Notarbartolo A, Davi G. Determinants of enhanced thromboxane biosynthesis in renal transplantation. Kidney Int 2001 59 1574-1579. 

Needleman, P., Raz, A., Munkes, M.S., Ferrendelli, J.A. and Sprecher, H. (1979). Triene prostaglandins prostacyclin and thromboxane biosynthesis and unique biological properties. Proc. Natl Acad. Sci., 76, 944—948... 

Almqvist, P.M., Kuenzig, M. and Schwartz, S.I. (1984). Treatment of experimental canine endotoxin shock with ibuprofen, a cyclo-oxygenase inhibitor. Circ. Shock, 13, 227-232 Gryglewski, R.J. (1978). Screening for inhibitors of prostaglandin and thromboxane biosynthesis. Adv. Lipid Res., 16, 327-44... 

Reilly, I.A.G., Doran, J.B., Smith, B. and FitzGerald, G.A. (1986). Increased thromboxane biosynthesis in a human model of platelet activation biochemical and functional consequences of selective inhibition of thromboxane synthase. Circulation, 73, 1300-1309... 

A phenyl phosphonate, sodium /J-benzyl-4-(l-oxo-2-(4-chlorobenzyl)-3-phenyl propyl) phenyl phosphonate (N-0164), inhibited thromboxane biosynthesis in human platelet microsomes with an ICjq of 2.2 X 10 M [110,111], However, this compound also acts as a prostaglandin receptor antagonist [112,113]. 

The non-acidic anti-inflammatory compound 2-isopropyl-3-nicotinylindole (L-8027) inhibits thromboxane biosynthesis [114-116] with simultaneous inhibition of PGE formation, indicating that the compound is not a specific inhibitor of thromboxane synthetase [117]. Metopyrone (2-methyl-l,2-di-3-pyridyl-l-propanone), which shares some structural features with L-8027, was reported to inhibit thromboxane formation in microsomes from human platelets and bovine lung [118]. 

Three vasodilating agents, hydralazine, dipyridamole and diazoxide, were reported to be weak inhibitors of thromboxane biosynthesis in human platelets [50,139-141]. Dipyridamole has also been shown to inhibit 3 5 -cyclic AMP phosphodiesterase of platelets [142]. 

Several factors are known to enhance the formation of thromboxanes, although their site of action may not necessarily be the enzyme, thromboxane synthetase. Some of these factors may be involved in the regulation of thromboxane biosynthesis in vivo. Thus, they may be of importance for the development of certain diseases a number of pathological conditions are known that seem to involve an increase in the thromboxane production by platelets or other cell types. These will be covered more in detail below (see section on Thromboxane production in pathological conditions). 

Calcium ionophores, such as A23187 and X538A, are known to stimulate thromboxane biosynthesis in platelets [168]. These compounds mobilize calcium from intracellular storage sites, leading to an increased calcium concentration in the cytosol. This in turn stimulates the release of arachidonic acid from its esterified storage form, and the subsequent conversion into prostaglandins and thromboxanes is thus increased [168]. 

The influence of cholesterol on thromboxane biosynthesis was briefly mentioned above. Cholesterol-rich platelets were shown to release more arachidonic acid than cholesterol-depleted ones upon stimulation with thrombin, and the subsequent conversion of the precursor into TXBj was also higher in the cholesterol-rich platelets [167], An increased thromboxane production from platelets in vivo in the rabbit has also been demonstrated after a cholesterol-rich diet [187]. 

The metabolic fates of TXA2 thus seem to be very complicated. A few years ago, TXB2 was almost automatically considered the end product of TXAj formation and a reliable parameter for monitoring thromboxane biosynthesis. Now it has become clear that under many circumstances it is only a minor and insignificant product. TXAj seems to be metabolized partially via different pathways and forms covalent derivatives with proteins, or is converted via the 15-hydroxy dehydrogenase pathway. The further fates of these products are not known. It is also possible that thromboxane formed in different cell types may undergo different fates. 

There are numerous pathological conditions in which derangements in thromboxane biosynthesis are supposed to contribute to the development of the symptoms. The well-known effects of TXA2, bronchoconstriction, vasoconstriction and induction of platelet aggregation, sjuggest the possible involvement of the compound in various pulmonary and cardiovascular events. The roles of thromboxanes in some respiratory diseases as well as in certain platelet disorders have already been discussed. 

Thromboxane production has been detected in several inflammatory conditions in inflamed joints such as urate arthritis [343] and rheumatoid arthritis [92] in carageenin induced pleurisy [91] and in burns [93,94,344]. The involvement of thromboxanes in burns has attracted particular attention. TXB2 has been demonstrated both in burn blister fluid and in lymph from the scalded limb [93,344] as well as in burned tissue [94] and the formation of the biologically active precursor, TXA 2, has been postulated as one factor responsible for the progressive dermal ischemia seen after burn injury, which may lead to extensive skin necrosis [94,344], The effects of three inhibitors of thromboxane biosynthesis on dermal ischemia were studied [345]. All compounds were found to increase dermal perfusion after scalding injury compared to untreated animals, which supports the theory of the deleterious influence of TXA2 upon dermal circulation in burned tissues. 

The renal production of thromboxanes seems to be very low normally. In certain conditions, however, the capacity of the kidney for thromboxane biosynthesis increases greatly. Thus, ureteral obstruction led to the appearance of TXA 2 as well as of large amounts of PGEj in the venous effluent of the affected kidney [346,347]. This biosynthesis was demonstrated both in the cortex and the medulla. The interplay between the enhanced production of the va.sodilatory PGEj and the vasoconstrictive TXA 2 was believed to be of importance for regulating the in vivo renal perfusion pressure in the hydronephrotic kidney. 

However, most pathological conditions, believed to involve derangements in the thromboxane biosynthesis - or in the thromboxane/prostacyclin balance - concern the cardiovascular system. A large number of diseases affecting this organ system have been studied in this respect, i.e. atherosclerosis, myocardial infarction, coronary artery disease with angina of various etiologies, thrombotic disorders, hemostatic defects, circulatory shock, ulcerative diseases, and so on. The possible roles of thromboxane and prostacyclin in the cardiovascular system have been discussed in several reviews, e.g. refs. 32, 33, 348-354. 

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