[HTML][HTML] The discovery of the leukotrienes

B Samuelsson - American journal of respiratory and critical care …, 2000 - atsjournals.org
B Samuelsson
American journal of respiratory and critical care medicine, 2000atsjournals.org
In a study of the transformation of polyunsaturated fatty acids in rabbit polymorphonuclear
leukocytes in 1976 it was discovered that arachidonic acid is oxygenated at C-5 (1).
Subsequently a number of derivatives, including leukotriene B4 (LTB4), were identified (2–
4). Extension of these studies led in 1979 to the discovery of the pivot epoxide intermediate,
LTA4 (5), and the elucidation of the structure of SRS-A (slowreacting substance of
anaphylaxis) as a group of cysteinyl-leukotrienes, namely LTC4, LTD4, and LTE4 (6–10) …
In a study of the transformation of polyunsaturated fatty acids in rabbit polymorphonuclear leukocytes in 1976 it was discovered that arachidonic acid is oxygenated at C-5 (1). Subsequently a number of derivatives, including leukotriene B4 (LTB4), were identified (2–4). Extension of these studies led in 1979 to the discovery of the pivot epoxide intermediate, LTA4 (5), and the elucidation of the structure of SRS-A (slowreacting substance of anaphylaxis) as a group of cysteinyl-leukotrienes, namely LTC4, LTD4, and LTE4 (6–10). Earlier work had shown that the prostaglandins are formed by oxygenation and further transformation of arachidonic acid and other polyunsaturated fatty acids (11). The first intermediate in the formation of prostaglandins, the endoperoxide PGG2, was isolated and identified in 1974 (12). At the same time we introduced the name cyclooxygenase for the enzyme catalyzing the transformation of arachidonic acid into PGG2 (12). However, the endoperoxides, PGG2 and PGH2, had some biological effects that could not be explained by their conversion to the known prostaglandins (12). This finding eventually led to the discovery of thromboxane A2, an unstable platelet-aggregating and vasoconstrictor substance (13). Subsequent work showed that the endoperoxide can also be converted into a derivative, prostacyclin (PGI2), with opposite biological effects (14). Prostaglandins E2 and I2 have strong proinflammatory effects.
Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the enzyme (cyclooxygenase) responsible for conversion of arachidonic acid into prostaglandins and thromboxanes (15). An induced form of the cyclooxygenase (COX-2) seems to play an important role in inflammation, thus opening the possibility of developing antiinflammatory NSAIDs that lack the side effects of the previous generation of such drugs (16, 17).
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