Prostaglandins and Leukotrienes

What do prostaglandins and leukotrienes have to do with lipids  

Prostaglandins are known to inhibit the aggregation of platelets. They may thus be of therapeutic value by preventing the formation of blood clots, which can cut off the blood supply to the brain or the heart and cause certain types of strokes and heart attacks. Even if this behavior were the only useful property of prostaglandins, it would justify considerable research effort. Heart attacks and strokes are two of the leading causes of death in industrialized countries. More recently, the study of prostaglandins has been a topic of great interest because of their possible antitumor and antiviral activity. 

The following Biochemical Gonnections box explores some connections among topics we have discussed in this chapter. 

Note the presence of a double bond at the third carbon atom from the end of the hydrocarbon tail. The omega system of nomenclature is based on numbering the double bonds from the last carbon in the fatty acid instead of the carbonyl group [the delta (A) system]. Omega is the last letter in the Greek alphabet. 

The omega-3 fatty acids inhibit the formation of certain prostaglandins and thromboxane A, which is similar in structure to prostaglandins. Thromboxane released by ruptured arteries causes other platelets to clump in the immediate area and to increase the size of the blood clot. Any disruption in thrombox- 

---

Calderwood, S.K., Bomstein, B., Famum, E.K.., Stevenson, M.A. (1989). Heat shock stimulates the release of arachidonic acid and the synthesis of prostaglandins and leukotriene B4 in mammalian cells. J. Cell. Physiol. 141, 325-333. 

Histamine Serotonin Platelet-activating factor (PAF) Eicosanoids (various prostaglandins and leukotrienes) C3a, C4a, and C5a from the complement system Bradykinin and fibrin split products from the coagulation system... 

FIGURE 55-3. Synthesis pathway for prostaglandins and leukotrienes. COX-2, cyclooxygenase enzyme 2 NSAIDs, nonsteroidal antiinflammatory drugs. (From DiPiro JT, Talbert RL, Yee GC, et al,... 

If there is a further exposure then the allergen crosslinks two IgE molecules, which triggers the release of histamine, prostaglandins and leukotrienes. These then produce the allergic response. 

The answer is b. (Hardman, p 1061.) Sulfasalazine consists of sul-fapyridine with 5-aminosalicylic acid linked by an azo- bond. This bond is broken by bacteria that release the salicylic acid, which is believed to be the active agent. Sulfa drugs or salicylic acid used alone is not as effective. The mechanism of action is unknown, but it is believed to be protective action on the mucosa by inhibition of the synthesis of prostaglandins and leukotrienes. 

Corticosteroids have antiinflammatory and immunosuppressive properties. They interfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophil and monocyte superoxide radical generation. 

Topical corticosteroids (Table 16-1) may halt synthesis and mitosis of DNA in epidermal cells and appear to inhibit phospholipase A, lowering the amounts of arachidonic acid, prostaglandins, and leukotrienes in the skin. These effects, coupled with local vasoconstriction, reduce erythema, pruritus, and scaling. As antipsoriatic agents, they are best used adjunc-tively with a product that specifically functions to normalize epidermal hyperproliferation. 

Taylor It is not prostaglandins because we can block the metabolism of arachidonate, and so prevent formation of prostaglandins and leukotrienes, but we still get activation of NCCE by vasopressin, indeed there is a modest potentiation of the response consistent with lesser degradation of the arachidonate. 

Peptideglycan biosynthesis Metabolism of Complex Lipids Glycerolipid metabolism Inositol phosphate metabolism Sphingophospholipid biosynthesis Phospholipid degradation Sphingoglycolipid metabolism Prostaglandin and leukotriene metabolism... 

Fatty acid derivatives include a large and diverse group of compounds named eicosanoids, which includes thromboxanes, prostaglandins and leukotrienes, all of which are biochemically derived from arachidonic acid (a long-chain polyunsaturated fatty acid). 

Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U. (1992). Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull (Tol o). 40(2) 387-91. Kobayashi M, Shqji N, Ohizumi Y. (1987). Gingerol, a novel cardiotonic agent, activates the Ca2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum. Biochim Biophys Acta. 903(1) 96-102. 

Kikuta Y, Kusunose E, Kusunose M. 2002. Prostaglandin and leukotriene omega-hydroxylases. Prostaglandins Other Lipid Mediat 68-69 345-362. 

Another important aspect of the inflammatory cascade is arachidonic acid metabolism, leading to the synthesis of the proinflammatory prostaglandins and leukotrienes. Through the formation of Upocortin, an inhibitor of phospholipase A2, glucocorticoids depress the release of arachidonic acid from phospholipids and hence the production of arachidonic acid metabolites. 

Hanaoka, and U. Sankawa. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diaryl-heptanoids. Chem Pharm Bull 1992 40(2) 387-391. 

Figure 8.9 Prostaglandins and leukotrienes are potent eicosanoid lipid mediators, derived from phospholipase-released arachidonic acids, that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and pharmacological actions are inhibited by clinically relevant nonsteroidal anti-inflammatory drugs.

C. Funk (2001). Prostaglandins and leukotrienes advances in eicosanoid biology. Science 294 1871-1875. 

They also influence the inflammatory response by reducing the prostaglandin and leukotriene synthesis that results from activation of enzyme phospholipase A. ... 

The effectiveness of ketoprofen at dosages of 100-300 mg/d is equivalent to that of other NSAIDs. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs in clinical efficacy. Its major adverse effects are on the gastrointestinal tract and the central nervous system (see common adverse effects above). 

---