Clin Biochem, Vol. 23, pp. 4 5 5 - 4 5 8 , 1990 P r i n t e d in Canada. All r i g h t s reserved.
0009-9120/90 $3.00 - .00 C o p y r i g h t c 1990 T h e C a n a d i a n Society of C l i n i c a l C h e m i s t s .
The Eicosanoids: A Historical Overview R. R O Y B A K E R Neurology
Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Eicosanoids are biologically active compounds derived from 20 carbon unsaturated fatty acids, among which arachidonic acid is a substrate of particular importance. The history of the eicosanoids dates back to the thirties, when new biologically active compounds were found in human seminal plasma. These "prostaglandins" were purified, and their structures and mechanisms of biosynthesis were elucidated in the early sixties. Other eicosanoids, including thromboxane A2, a potent platelet aggregating agent, and prostacyclin, an antagonist to thromboxane A 2, w e r e discovered in the seventies. The inhibitory actions of acetylsalicylic acid on eicosanoid synthesis were also uncovered at this time. In 1979, a new metabolic sequence leading to the synthesis of a new group of eicosanoids, called leukotrienes, was reported. The leukotrienes have several biological activities, including the mediation of bronchoconstriction in allergic response. The eicosanoids comprise a diverse group of biologically active compounds; many of these arise from arachidonic acid, and are associated with injury, allergic responses, and platelet aggregation.
KEY WORDS: eicosanoids; arachidonic acid; prostaglandin E2; thromboxane A2; prostacyclin; leukotrienes; acetylsalicylic acid.
Discovery and c h a r a c t e r i z a t i o n o f prostaglandins E
icosanoids comprise a remarkable group of compounds that are involved in a variety of clinically important areas including, inflammation, fever, thrombosis, and allergic and immune responses. The term eicosanoid, introduced in 1979, refers to biologically active compounds derived from 20 carbon, unsaturated fatty acids (1). The most prominent of these is arachidonic acid (I, see Figure 1), a common fatty acid found in phosphoglycerides of mammalian cell membranes (2), The history of the eicosanoids dates back to 1930 when Kurzrok and Lieb, studying artificial insemination, found that h u m a n seminal fluid could relax or contract uterine strips taken from patients who were fertile or infertile, respectively (3). This observation did not stimulate a search for a new biologically active factor, because acetylcholine (which was very popular at the time) was thought to be responsible. In the thirties, much interest was shown
Correspondence: Dr. R. Roy Baker, Clinical Science Division, 6368 Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8. Manuscript received November 11, 1989; revised January 28, 1990; accepted January 31, 1990. CLINICAL BIOCHEMISTRY,VOLUME 23, OCTOBER 1990
in the biogenic amines. These were found to have remarkable effects on the circulation, or excised organs, of experimental animals (3). The use of the bioassay for quantitating and identifying certain active principles was rapidly developed (4). In 1933 and 1935, Goldblatt observed the effects of h u m a n seminal plasma on isolated organs, or following injection into animals (5,6). He noted that the principle could be distinguished from other known active compounds. Von Euler made similar, independent observations in 1934, using sheep vesicular gland extracts and h u m a n seminal plasma (7). Through Von Euler's early chemical characterization of the active compound, he found that the activity could be extracted into lipid solvents from acidified solutions, and that the activity was soluble in an aqueous alkaline medium. Thus, the active compound had the properties of a fatty acid, and migrated toward the anode during electrophoresis, at pH 6.5 (4). This indicated a new kind of active compound, which von Euler called prostaglandin, as it was found in prostate and vesicular gland. In 1947, Von Euler collaborated with Sune Bergstrbm, a specialist in lipid chemistry. Bergstrbm began to purify (this took a number of years) prostaglandin from a concentrate of sheep vesicular glands; he found the activity associated with a fraction containing unsaturated hydroxy fatty acids (8). The small quantities of prostaglandin made the purification difficult. In 1960, however, Sjovall and Bergstrbm (9,10) isolated two prostaglandins, PGE1 and PGFI~. The rabbit duodenum bioassay was used to follow the prostaglandins through the purification procedure. Using chemical characterization and gas chromatography/mass spectrometry, the structures of PGE1 and PGFI~ were elucidated as unsaturated, 20 carbon hydroxy carboxylic acids, containing a five carbon ring. BergstrSm's group isolated and characterized other prostaglandins: PGE e (II) and PGE 3 from sheep vesicular glands, and PGF2~ (III) and PGF3~ from sheep and bovine lung (8). Certain of these six primary prostaglandins were found in other tissues, although h u m a n seminal fluid was the richest source (8). T h e b i o s y n t h e s i s o f prostaglandins The first studies on the biosynthesis of the prostaglandins were carried out by Eliasson (11), who 455
BAKER
OOH
OH i~~/,~.C
r~-"~COOH
JC5H~I
%
Arachidonic Acid
OH
OH
T~A 2 /
LTB 4 X OH H / / ,/J"'
["
-'. o
I
o ( ~ . y - "~"",,.~"~'~,"/~ COO H C5Hll OH OH
OH r'~ -''~cOOH HO/L O ~-1,,,.,~"~/C5H 11 OH
PGE 2 II
"'-/~COOH C5Hll OH
OH
"~,=/- b5Nll
LTC4xI NHCOCH2CH2~HCOOH NH2
COOH
OH ..H ~..-
~ C O O H I'~.=/__csHH
CHCONHCH2COOH I
NH2
LTD 4 XI1
PGI^ Vll z O
QOH
PGG 2 IV
S-IH2
OH
PGF~ Ill z~
O"7"~-'"~COOH
I ° CHCONHCH2COOH
''" .~_-~/JCsHH OH
~
OH~ ~ C O O H "" OH
COOH
S-CH I
TxB 2 Vl
f pq;
OH
OO H
HO
CH- COOH
LTE 4 XIII
6-keto-PGF1. VIII H
COOH
I'~,,_~_./~05H11H S-~H2
OH
/~V~,..-.
H
I
NH2
OOH / COOH
5-HPETE IX F i g u r e 1 - - C h e m i c a l structures of arachidonic acid and its metabolites. The r o m a n n u m e r a l s are employed to identify these compounds in the text.
incubated an homogenate of sheep vesicular glands and found, as a result, an increased quantity of active compound. This effect was increased by the presence of phospholipase A2 in the incubation medium. As arachidonic acid is a common 20 carbon, polyunsaturated fatty acid present in tissue phospholipids, attention was directed toward this fatty acid as a potential precursor. Van Dorp synthesized radioactive arachidonic acid; the laboratories of Van Dorp and Bergstrbm demonstrated the production of radioactive PGE 2 as the main product formed from this substrate in incubations with homogenates of sheep vesicular glands (12,13). Studying the mechanism of their biosynthesis, Samuelsson and Van Dorp demonstrated that all three oxygens found in the prostaglandins were derived from molecular oxygen, and that a dioxygenase activity was in-
456
volved (14,16). The intermediate endoperoxide (PGG2, IV) was isolated and characterized by Hamberg and Samuelsson (17). Samuelsson (18) described the action of the enzyme cyclooxygenase in the formation of PGG2, later converted into the hydroxyendoperoxide PGH2. PGH2 is used in the synthesis of the classic prostaglandins, PGE2 (II) and PGF2~ (III). Interest centered on inhibitors of cyclo-oxygenase activity. Vane, using lung (19), and Smith and Willis, using platelets (20), found that the cyclooxygenase was inhibited by acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs. T h r o m b o x a n e s and prostacylin Platelets were of further interest because they formed an eicosanoid from arachidonic acid which
CLINICAL BIOCHEMISTRY, VOLUME 23, OCTOBER 1990
THE ECOSANOIDS: A HISTORICALOVERVIEW was neither PGE2 nor PGF2,. This new eicosanoid was thromboxane A 2 (TxA 2, V), an extremely labile compound, rapidly metabolized to its more stable derivative, TxB 2 (VI). TxA 2 is an extremely potent platelet aggregating agent, initially described by H amb er g and Samuelsson (21,22). TxA 2 is also known as rabbit aorta contracting substance (23), as it is a vasoconstrictor. PG H 2 can be converted into this eicosanoid by the enzyme thromboxane synthetase. Another product formed from PGH2 was discovered by Vane and his coworkers during incubation of the endoperoxide with blood vessel preparations (24). This new eicosanoid was prostacyclin (VII) or PGI2. PGI2 can serve as antagonist to TxA 2, because PGI 2 is a powerful inhibitor of platelet aggregation. Like TxA 2, PGI 2 is also unstable, with a short hal f life. PGI 2 is broken down to 6-keto-PGFl~ (VIII), a compound described by Pace-Asciak and Wolfe (25) and Pace-Asciak (26). Thus PG H 2, derived from arachidonic acid by cyclooxygenase activity, can be converted into PGE 2, PGF2,, TxA2, or PGI 2.
The leukotrienes In 1967, H a m b e r g and Samuelsson studied the plant enzyme lipoxygenase, to investigate oxygen insertion into p o l yuns a t ur at ed fatty acids (27). They found t h a t platelets also have 12-1ipoxygenase activity and can convert arachidonic acid into 12hydroperoxyeicosatetraenoic acid (12-HPETE) (21). Polymorphonuclear leukocytes possess 5-1ipoxygenase, which will produce 5-HPETE (IX), using arachidonic acid as substrate. Borgeat and Samuelsson found t h a t 5-HPETE can be subsequently converted to compounds called leukotrienes (28): so named because of their three conjugated double bonds and their origin in leukocytes. The tripeptide glutathione is involved in the formation of leukotriene C4 (LTC4, XI), which gives rise to LTD4 (XII) and LTE 4 (XIII). LTC4, LTD4, and LTE 4 were classifted earlier as slow reacting substance of anaphylaxis (SRS-A). In lung, SRS-A will cause contraction of smooth muscle in response to immunological challenge. Thus, leukotrienes are likely mediators of bronchoconstriction in a s t hm a {29). The leukotriene, LTB 4 (X), is highly chemotactic for polymorphonuclear leukocytes (30).
Summary The eicosanoids are a r e m a r k a b l y diverse group of biologically active compounds. Their formation depends upon the release of polyunsaturates, usually arachidonic acid, from m e m b r a n e phospholipids. This is mediated by phospholipase activities (31), which will rise after a particular cellular stimulus is administered. These stimuli can be associated with injury, immunologic or allergic responses, and platelet aggregation. Depending upon the tis-
CLINICAL BIOCHEMISTRY, VOLUME 23, OCTOBER 1990
sue or cell involved, different eicosanoids will be produced. These can have detrimental influences on tissue function, and may contribute to the pathology seen in diseases where the above responses are prominent.
References 1. Corey EJ, Niwa H, Falck JR, Mioskowski C, Arai Y, Marfat A. Recent studies on the chemical synthesis of eicosanoids. Adv Prostaglandin Thromboxane Res 1980; 6: 19-25. 2. White DA. The phospholipid composition of mammalian tissues. In: Ansell GB, Hawthorne JN, Dawson RMC, eds. Form and function of phospholipids. Pp. 441-82. Amsterdam: Elsevier Scientific, 1973. 3. Von Euler US. Welcoming address. In: BergstrSm S, Samuelsson B, eds. Prostaglandins, Proceedings of the Second Nobel Symposium. Pp. 17-20. New York: Interscience Publishers, 1967. 4. Von Euler US, Eliasson R. Historical survey. In: DeStevens G, ed. Prostaglandins. Pp. 1-5. New York: Academic Press, 1967. 5. Goldblatt MW. A depressor substance in seminal fluid. J Soc Chem Ind (Lond) 1933; 52: 1056-7. 6. Goldblatt MW. Properties of human seminal plasma. J Physiol (Lond) 1935; 84: 208-18. 7. Von Euler US. Zur kenntnis der pharmakologischen wirkungen yon nativsekreten und extrakten mannlicher accessoricher Geschechtsdrusen. NaunynSchmiedebergs Arch Pharmacol 1934; 175: 78-84. 8. Bergstr~m S. Isolation, structure and action of the prostaglandins. In: Bergstr~m S, Samuelsson B, eds. Prostaglandins. Pp. 21-30. New York: Interscience Publishers, 1967. 9. BergstrSm S, Sjovall J. I. The isolation of prostaglandin F from sheep prostate glands. Acta Chem Scand 1960; 14: 1693-700. 10. Bergstr6m S, Sjovall J. II. The isolation of prostaglandin E from sheep prostate glands. Acta Chem Scand 1960; 14: 1701-5. 11. Eliasson R. Studies on the prostaglandin: occurrence, formation and biological actions. Acta Physiol Scand 1959; 46 (Suppl. 158): 1-73. 12. Van Dorp DA, Beerthuis RK, Nugteren DH, Vonkeman H. The biosynthesis of prostaglandins. Biochim Biophys Acta 1964; 90: 204-7. 13. Bergstr~m S, Danielsson H, Samuelsson B. The enzymatic formation of prostaglandin E2 from arachidonic acid. Biochim Biophys Acta 1964; 90: 207-10. 14. Samuelsson B. On the incorporation of oxygen in the conversion of 8,11,14-eicosatrienoic acid into prostaglandin E~. J Am Chem Soc 1965; 87: 3011-3. 15. Ryhage R, Samuelsson B. The origin of oxygen incorporated during the biosynthesis of prostaglandin El. Biochem Biophys Res Commun 1965; 19: 279-82. 16. Nugteren DH, Van Dorp DA. The participation of molecular oxygen in the biosynthesis of prostaglandins. Biochim Biophys Acta 1965; 98: 654-6. 17. Hamberg M, Samuelsson B. Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis. Proc Nat Acad Sci USA 1973; 70: 899903. 18. Samuelsson B. Prostaglandin endoperoxides and thromboxanes: short lived bioregulators. In: Crabb6 P, ed. Prostaglandin research. Pp. 17-46. New York: Academic Press, 1977.
457
BAKER 19. Van JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 232-5. 20. Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nature 1971; 231: 235-7. 21. Hamberg M, Samuelsson B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci USA 1974; 71: 3400-4. 22. Hamberg M, Svensson J, Samuelsson B. A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72: 2994-8. 23. Piper PJ, Vane JR. Release of additional factors in anaphylaxis and its antagonism by anti-inflammatory drugs. Nature 1969; 223: 29-35. 24. Gryglewski RJ, Bunting S, Moncada S, Flower RJ, Vane JR. Arterial walls are protected against deposition ofplatelet thrombi by a substance Cprostaglandin x) which they make from prostaglandin endoperoxides. Prostaglandins 1976; 12: 685-714.
458
25. Pace-Asciak C, Wolfe LS. A novel prostaglandin derivative formed from arachidonic acid by rat stomach homogenates. Biochemistry 1971; 10: 3657-64. 26. Pace-Asciak C. Isolation, structure, and biosynthesis of 6-keto prostaglandin FI~ in the rat stomach. J Am Chem Soc 1976; 98: 2348-9. 27. Hamberg M, Samuelsson B. On the mechanism of the biosynthesis of prostaglandins E 1 and F,,,. J Biol Chem 1967; 242: 5336--43. 28. Borgeat P, Samuelsson B. Metabolism of arachidonic acid in polymorphonuclear leukocytes. J Biol Chem 1979; 254: 7865-9. 29. Dahl~n SE, Hedgvist P, Hammarstrom S, Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature 1980; 288: 484-6. 30. Ford-Hutchison AW, Bray MA, Boig MV, Shipley ME, Smith MJH. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980; 286: 264-5. 31. Wolfe LS, Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids. J Neurochem 1982; 38: 1-14.
CLINICAL BIOCHEMISTRY, VOLUME 23, OCTOBER 1990
0009-9120/90 $3.00 - .00 C o p y r i g h t c 1990 T h e C a n a d i a n Society of C l i n i c a l C h e m i s t s .
The Eicosanoids: A Historical Overview R. R O Y B A K E R Neurology
Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Eicosanoids are biologically active compounds derived from 20 carbon unsaturated fatty acids, among which arachidonic acid is a substrate of particular importance. The history of the eicosanoids dates back to the thirties, when new biologically active compounds were found in human seminal plasma. These "prostaglandins" were purified, and their structures and mechanisms of biosynthesis were elucidated in the early sixties. Other eicosanoids, including thromboxane A2, a potent platelet aggregating agent, and prostacyclin, an antagonist to thromboxane A 2, w e r e discovered in the seventies. The inhibitory actions of acetylsalicylic acid on eicosanoid synthesis were also uncovered at this time. In 1979, a new metabolic sequence leading to the synthesis of a new group of eicosanoids, called leukotrienes, was reported. The leukotrienes have several biological activities, including the mediation of bronchoconstriction in allergic response. The eicosanoids comprise a diverse group of biologically active compounds; many of these arise from arachidonic acid, and are associated with injury, allergic responses, and platelet aggregation.
KEY WORDS: eicosanoids; arachidonic acid; prostaglandin E2; thromboxane A2; prostacyclin; leukotrienes; acetylsalicylic acid.
Discovery and c h a r a c t e r i z a t i o n o f prostaglandins E
icosanoids comprise a remarkable group of compounds that are involved in a variety of clinically important areas including, inflammation, fever, thrombosis, and allergic and immune responses. The term eicosanoid, introduced in 1979, refers to biologically active compounds derived from 20 carbon, unsaturated fatty acids (1). The most prominent of these is arachidonic acid (I, see Figure 1), a common fatty acid found in phosphoglycerides of mammalian cell membranes (2), The history of the eicosanoids dates back to 1930 when Kurzrok and Lieb, studying artificial insemination, found that h u m a n seminal fluid could relax or contract uterine strips taken from patients who were fertile or infertile, respectively (3). This observation did not stimulate a search for a new biologically active factor, because acetylcholine (which was very popular at the time) was thought to be responsible. In the thirties, much interest was shown
Correspondence: Dr. R. Roy Baker, Clinical Science Division, 6368 Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8. Manuscript received November 11, 1989; revised January 28, 1990; accepted January 31, 1990. CLINICAL BIOCHEMISTRY,VOLUME 23, OCTOBER 1990
in the biogenic amines. These were found to have remarkable effects on the circulation, or excised organs, of experimental animals (3). The use of the bioassay for quantitating and identifying certain active principles was rapidly developed (4). In 1933 and 1935, Goldblatt observed the effects of h u m a n seminal plasma on isolated organs, or following injection into animals (5,6). He noted that the principle could be distinguished from other known active compounds. Von Euler made similar, independent observations in 1934, using sheep vesicular gland extracts and h u m a n seminal plasma (7). Through Von Euler's early chemical characterization of the active compound, he found that the activity could be extracted into lipid solvents from acidified solutions, and that the activity was soluble in an aqueous alkaline medium. Thus, the active compound had the properties of a fatty acid, and migrated toward the anode during electrophoresis, at pH 6.5 (4). This indicated a new kind of active compound, which von Euler called prostaglandin, as it was found in prostate and vesicular gland. In 1947, Von Euler collaborated with Sune Bergstrbm, a specialist in lipid chemistry. Bergstrbm began to purify (this took a number of years) prostaglandin from a concentrate of sheep vesicular glands; he found the activity associated with a fraction containing unsaturated hydroxy fatty acids (8). The small quantities of prostaglandin made the purification difficult. In 1960, however, Sjovall and Bergstrbm (9,10) isolated two prostaglandins, PGE1 and PGFI~. The rabbit duodenum bioassay was used to follow the prostaglandins through the purification procedure. Using chemical characterization and gas chromatography/mass spectrometry, the structures of PGE1 and PGFI~ were elucidated as unsaturated, 20 carbon hydroxy carboxylic acids, containing a five carbon ring. BergstrSm's group isolated and characterized other prostaglandins: PGE e (II) and PGE 3 from sheep vesicular glands, and PGF2~ (III) and PGF3~ from sheep and bovine lung (8). Certain of these six primary prostaglandins were found in other tissues, although h u m a n seminal fluid was the richest source (8). T h e b i o s y n t h e s i s o f prostaglandins The first studies on the biosynthesis of the prostaglandins were carried out by Eliasson (11), who 455
BAKER
OOH
OH i~~/,~.C
r~-"~COOH
JC5H~I
%
Arachidonic Acid
OH
OH
T~A 2 /
LTB 4 X OH H / / ,/J"'
["
-'. o
I
o ( ~ . y - "~"",,.~"~'~,"/~ COO H C5Hll OH OH
OH r'~ -''~cOOH HO/L O ~-1,,,.,~"~/C5H 11 OH
PGE 2 II
"'-/~COOH C5Hll OH
OH
"~,=/- b5Nll
LTC4xI NHCOCH2CH2~HCOOH NH2
COOH
OH ..H ~..-
~ C O O H I'~.=/__csHH
CHCONHCH2COOH I
NH2
LTD 4 XI1
PGI^ Vll z O
QOH
PGG 2 IV
S-IH2
OH
PGF~ Ill z~
O"7"~-'"~COOH
I ° CHCONHCH2COOH
''" .~_-~/JCsHH OH
~
OH~ ~ C O O H "" OH
COOH
S-CH I
TxB 2 Vl
f pq;
OH
OO H
HO
CH- COOH
LTE 4 XIII
6-keto-PGF1. VIII H
COOH
I'~,,_~_./~05H11H S-~H2
OH
/~V~,..-.
H
I
NH2
OOH / COOH
5-HPETE IX F i g u r e 1 - - C h e m i c a l structures of arachidonic acid and its metabolites. The r o m a n n u m e r a l s are employed to identify these compounds in the text.
incubated an homogenate of sheep vesicular glands and found, as a result, an increased quantity of active compound. This effect was increased by the presence of phospholipase A2 in the incubation medium. As arachidonic acid is a common 20 carbon, polyunsaturated fatty acid present in tissue phospholipids, attention was directed toward this fatty acid as a potential precursor. Van Dorp synthesized radioactive arachidonic acid; the laboratories of Van Dorp and Bergstrbm demonstrated the production of radioactive PGE 2 as the main product formed from this substrate in incubations with homogenates of sheep vesicular glands (12,13). Studying the mechanism of their biosynthesis, Samuelsson and Van Dorp demonstrated that all three oxygens found in the prostaglandins were derived from molecular oxygen, and that a dioxygenase activity was in-
456
volved (14,16). The intermediate endoperoxide (PGG2, IV) was isolated and characterized by Hamberg and Samuelsson (17). Samuelsson (18) described the action of the enzyme cyclooxygenase in the formation of PGG2, later converted into the hydroxyendoperoxide PGH2. PGH2 is used in the synthesis of the classic prostaglandins, PGE2 (II) and PGF2~ (III). Interest centered on inhibitors of cyclo-oxygenase activity. Vane, using lung (19), and Smith and Willis, using platelets (20), found that the cyclooxygenase was inhibited by acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs. T h r o m b o x a n e s and prostacylin Platelets were of further interest because they formed an eicosanoid from arachidonic acid which
CLINICAL BIOCHEMISTRY, VOLUME 23, OCTOBER 1990
THE ECOSANOIDS: A HISTORICALOVERVIEW was neither PGE2 nor PGF2,. This new eicosanoid was thromboxane A 2 (TxA 2, V), an extremely labile compound, rapidly metabolized to its more stable derivative, TxB 2 (VI). TxA 2 is an extremely potent platelet aggregating agent, initially described by H amb er g and Samuelsson (21,22). TxA 2 is also known as rabbit aorta contracting substance (23), as it is a vasoconstrictor. PG H 2 can be converted into this eicosanoid by the enzyme thromboxane synthetase. Another product formed from PGH2 was discovered by Vane and his coworkers during incubation of the endoperoxide with blood vessel preparations (24). This new eicosanoid was prostacyclin (VII) or PGI2. PGI2 can serve as antagonist to TxA 2, because PGI 2 is a powerful inhibitor of platelet aggregation. Like TxA 2, PGI 2 is also unstable, with a short hal f life. PGI 2 is broken down to 6-keto-PGFl~ (VIII), a compound described by Pace-Asciak and Wolfe (25) and Pace-Asciak (26). Thus PG H 2, derived from arachidonic acid by cyclooxygenase activity, can be converted into PGE 2, PGF2,, TxA2, or PGI 2.
The leukotrienes In 1967, H a m b e r g and Samuelsson studied the plant enzyme lipoxygenase, to investigate oxygen insertion into p o l yuns a t ur at ed fatty acids (27). They found t h a t platelets also have 12-1ipoxygenase activity and can convert arachidonic acid into 12hydroperoxyeicosatetraenoic acid (12-HPETE) (21). Polymorphonuclear leukocytes possess 5-1ipoxygenase, which will produce 5-HPETE (IX), using arachidonic acid as substrate. Borgeat and Samuelsson found t h a t 5-HPETE can be subsequently converted to compounds called leukotrienes (28): so named because of their three conjugated double bonds and their origin in leukocytes. The tripeptide glutathione is involved in the formation of leukotriene C4 (LTC4, XI), which gives rise to LTD4 (XII) and LTE 4 (XIII). LTC4, LTD4, and LTE 4 were classifted earlier as slow reacting substance of anaphylaxis (SRS-A). In lung, SRS-A will cause contraction of smooth muscle in response to immunological challenge. Thus, leukotrienes are likely mediators of bronchoconstriction in a s t hm a {29). The leukotriene, LTB 4 (X), is highly chemotactic for polymorphonuclear leukocytes (30).
Summary The eicosanoids are a r e m a r k a b l y diverse group of biologically active compounds. Their formation depends upon the release of polyunsaturates, usually arachidonic acid, from m e m b r a n e phospholipids. This is mediated by phospholipase activities (31), which will rise after a particular cellular stimulus is administered. These stimuli can be associated with injury, immunologic or allergic responses, and platelet aggregation. Depending upon the tis-
CLINICAL BIOCHEMISTRY, VOLUME 23, OCTOBER 1990
sue or cell involved, different eicosanoids will be produced. These can have detrimental influences on tissue function, and may contribute to the pathology seen in diseases where the above responses are prominent.
References 1. Corey EJ, Niwa H, Falck JR, Mioskowski C, Arai Y, Marfat A. Recent studies on the chemical synthesis of eicosanoids. Adv Prostaglandin Thromboxane Res 1980; 6: 19-25. 2. White DA. The phospholipid composition of mammalian tissues. In: Ansell GB, Hawthorne JN, Dawson RMC, eds. Form and function of phospholipids. Pp. 441-82. Amsterdam: Elsevier Scientific, 1973. 3. Von Euler US. Welcoming address. In: BergstrSm S, Samuelsson B, eds. Prostaglandins, Proceedings of the Second Nobel Symposium. Pp. 17-20. New York: Interscience Publishers, 1967. 4. Von Euler US, Eliasson R. Historical survey. In: DeStevens G, ed. Prostaglandins. Pp. 1-5. New York: Academic Press, 1967. 5. Goldblatt MW. A depressor substance in seminal fluid. J Soc Chem Ind (Lond) 1933; 52: 1056-7. 6. Goldblatt MW. Properties of human seminal plasma. J Physiol (Lond) 1935; 84: 208-18. 7. Von Euler US. Zur kenntnis der pharmakologischen wirkungen yon nativsekreten und extrakten mannlicher accessoricher Geschechtsdrusen. NaunynSchmiedebergs Arch Pharmacol 1934; 175: 78-84. 8. Bergstr~m S. Isolation, structure and action of the prostaglandins. In: Bergstr~m S, Samuelsson B, eds. Prostaglandins. Pp. 21-30. New York: Interscience Publishers, 1967. 9. BergstrSm S, Sjovall J. I. The isolation of prostaglandin F from sheep prostate glands. Acta Chem Scand 1960; 14: 1693-700. 10. Bergstr6m S, Sjovall J. II. The isolation of prostaglandin E from sheep prostate glands. Acta Chem Scand 1960; 14: 1701-5. 11. Eliasson R. Studies on the prostaglandin: occurrence, formation and biological actions. Acta Physiol Scand 1959; 46 (Suppl. 158): 1-73. 12. Van Dorp DA, Beerthuis RK, Nugteren DH, Vonkeman H. The biosynthesis of prostaglandins. Biochim Biophys Acta 1964; 90: 204-7. 13. Bergstr~m S, Danielsson H, Samuelsson B. The enzymatic formation of prostaglandin E2 from arachidonic acid. Biochim Biophys Acta 1964; 90: 207-10. 14. Samuelsson B. On the incorporation of oxygen in the conversion of 8,11,14-eicosatrienoic acid into prostaglandin E~. J Am Chem Soc 1965; 87: 3011-3. 15. Ryhage R, Samuelsson B. The origin of oxygen incorporated during the biosynthesis of prostaglandin El. Biochem Biophys Res Commun 1965; 19: 279-82. 16. Nugteren DH, Van Dorp DA. The participation of molecular oxygen in the biosynthesis of prostaglandins. Biochim Biophys Acta 1965; 98: 654-6. 17. Hamberg M, Samuelsson B. Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis. Proc Nat Acad Sci USA 1973; 70: 899903. 18. Samuelsson B. Prostaglandin endoperoxides and thromboxanes: short lived bioregulators. In: Crabb6 P, ed. Prostaglandin research. Pp. 17-46. New York: Academic Press, 1977.
457
BAKER 19. Van JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 232-5. 20. Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nature 1971; 231: 235-7. 21. Hamberg M, Samuelsson B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci USA 1974; 71: 3400-4. 22. Hamberg M, Svensson J, Samuelsson B. A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72: 2994-8. 23. Piper PJ, Vane JR. Release of additional factors in anaphylaxis and its antagonism by anti-inflammatory drugs. Nature 1969; 223: 29-35. 24. Gryglewski RJ, Bunting S, Moncada S, Flower RJ, Vane JR. Arterial walls are protected against deposition ofplatelet thrombi by a substance Cprostaglandin x) which they make from prostaglandin endoperoxides. Prostaglandins 1976; 12: 685-714.
458
25. Pace-Asciak C, Wolfe LS. A novel prostaglandin derivative formed from arachidonic acid by rat stomach homogenates. Biochemistry 1971; 10: 3657-64. 26. Pace-Asciak C. Isolation, structure, and biosynthesis of 6-keto prostaglandin FI~ in the rat stomach. J Am Chem Soc 1976; 98: 2348-9. 27. Hamberg M, Samuelsson B. On the mechanism of the biosynthesis of prostaglandins E 1 and F,,,. J Biol Chem 1967; 242: 5336--43. 28. Borgeat P, Samuelsson B. Metabolism of arachidonic acid in polymorphonuclear leukocytes. J Biol Chem 1979; 254: 7865-9. 29. Dahl~n SE, Hedgvist P, Hammarstrom S, Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature 1980; 288: 484-6. 30. Ford-Hutchison AW, Bray MA, Boig MV, Shipley ME, Smith MJH. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980; 286: 264-5. 31. Wolfe LS, Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids. J Neurochem 1982; 38: 1-14.
CLINICAL BIOCHEMISTRY, VOLUME 23, OCTOBER 1990
