The Leukotrienes, Highly Biologically Active Substance Involved in Allergy and Inflammation (1982)

Abstract Arachidonic acid, a fourfold unsaturated C 20 ‐fatty acid, has attracted interest over the last 15 years far beyond the bounds of nutritional research. It forms an essential acyl component of the phospholopids in all animal cells. The long know fact that certain unsaturated fatty acids must be contained in the diet in order to ensure normal function of the organism has been explained by the discovery of a broad palette of biologically highly active oxidation products of arachidonic acid, a cascade, as it is often referred to. Arachidonic acid is formed in organisms from linoleic and linolenic acids, which belong to the so‐called essential fatty acids. As early as 1935 Ulf von Euler was able to detect a substance in semen which caused smooth muscles to contract. This factor, which was later isolated in pure form, was termed prostaglandin. The number of prostaglandins, including the synthetically obtained analogues, then rapidly increased. Prostaglandins are biosynthesized from arachidonic acid and similar C 20 ‐fatty acids by enzymatic oxidation with a cyclooxygenase. Its activity is inhibited by acetylsalicylic acid, indomethazine, and other substances, because these relieve or cure inflammations arising from the action of certain prostaglandins. After the prostaglandins, the thromboxanes, which promote aggregation of blood platelets and thus cause thrombosis, were discoverd as further metabolic products of arachidonic acid. In a well‐balanced equilibrium the thromboxanes have a biological effect completely opposite to that of prostacyclin, discovered soon after this, which inhibits platelet aggregation. Both of these biologically active substances are metabolites of arachidonic acid, and are formed in the course of the cyclizing oxidation. Aspirin and substances having a similar mode of action, therefore have an influence on thrombosis. There are, however, contraction processes and inflammation symptoms which do not respond to these substances, but to steroid hormones (cortisone). For symptoms of this type, to which asthma also belongs, the most recently discovered metabolic products of arachidonic acid are probably highly decisive; they are formed by another enzymatic route via a hydroperoxide of arachidonic acid. These compounds are formed in leukocytes and contain the triply unsaturated structural element of a triene and were, therefore, termed leukotrienes. Their astonishingly high histamine‐like activity in producing contraction of lung capillaries, their marked property of making capillary vessels permeable to blood plasma, i.e. of generating oedema, the ability of leukotriene LTB 4 to cause adherence of human leukocytes and their adhesion to the endothelium, make the leukotrienes chemical mediators in allergies and inflammations, and produce biological effects when present at minute concentrations. In the following article one of the three scientists who were awarded this years Nobel prize for medicine and physiology, and who provided an explanation for this extraordinarily interesting class of natural products, gives an account of the conversion of arachidonic acid into the labile epoxide LTA 4 and further into the dihydroxy compound LTB 4 , or the glutathione cysteinylglycine and cysteine conjugates LTC 4 . LTD 4 , and LTE 4 , respectively, as well as of the physiological‐pathological implications. The two other prize winners in this area of biologically active compounds, which are often referred to as eicosanoids, are Samuelsson 's teacher Sune Bergstöm and the Britain John Vane .