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Interactions between arachidonic and eicosapentaenoic acids during their dioxygenase-dependent peroxidation
PROSTAGLANDINSLEUKOTRIENES ANDESSENTIALFATTYACIDS
Interactions Between Arachidonic and Eicosapentaenoic Acids During Their Dioxygenase-dependent Peroxidation M. Lagarde, E. Vericel, M. Croset. C. Calzada, J.C. Bordet* and M. Guichardant” INSERM U 352, Chirnie Biologique INSA de Lyon and *Lnboratoire France (Reprint requests to ML)
d’Ht%nobiologie,
FacultP A1e.vi.sCarrel, Lyon,
ABSTRACT. Eicosapentaenoic acid (EPA), a major polyunsaturated fatty acid of fish has been widely proposed as a potential nutrient for decreasing platelet-endothelial cell interactions and the subsequent atherogenesis and thrombogenesis. This is mainly based upon the decrease of arachidonic acid (AA) oxygenation into bioactive molecules like thromboxane A*. In addition, EPA may be oxygenated into its own active derivatives via cell dioxygenases. We report evidence for the requirement of specific peroxides, adequately provided by AA, to allow EPA to be oxygenated into its bioactive products like prostaglandin I,, a prostacyclin mimetic. On the other hand, we present some data that argue for a decreased basal AA dioxygenation (specific peroxidation) by small concentrations of EPA. The interactions between AA and EPA are then dual, EPA being able to counteract AA oxygenation whereas EPA requires AA to be efficiently oxygenated.
INTRODUCTION Arachidonic acid (AA, 20:4n-6) is the major polyunsatured fatty acid (PUFA) in animal tissues, except for limited areas in brain structures like the retina where the most abundant PUFA is docosahexaenoic acid (DHA, 22:6n-3). also called cervonic acid for this preferential location. Eicosapentaenoic acid (EPA, 20:5n-3) is found in low proportions in animal tissues, except when ingested in large amounts from marine oil or marine meat. In this case. it accumulates in most tissues together with DHA ingested in similar amounts from marine sources. The accumulation of EPA, following n-3 fatty acids, has been extensively studied, especially in blood and vascular cells where it is assumed to regulate AA metabolism Cl). The chemical structure of EPA resembles that of AA with only one additional double bond at carbon 17. This makes EPA a fairly good candidate for competing with the cell metabolism of AA. Indeed, EPA accumulates in cell glycerophospholipids mainly at the expense of AA and counteracts part of the specific oxygenation of AA via the cell dioxygenases, cyclooxygenase and lipoxygenases (2, 3). EPA has also the potential to be oxygenated into prostanoids and lipoxygenase products. In this paper, we present evidence for unidirectional interactions between AA and EPA. In platelets and endothelial cells. the specific oxygenation of EPA is markedly potentiated by AA via AA hydroperoxides whereas EPA may decrease the peroxidation of AA.
POTENTIATION AA
OF EPA OXYGENATION
BY
Although it is known that EPA may compete with the cyclooxygenation of AA in platelets and endothelial cells (4), presumably as a competitive inhibitor, the reverse is not true. When intact platelets are incubated with EPA alone, very few cyclooxygenase/thromboxane synthase products are formed, but those products appear when AA is coincubated with EPA (5). Dihomo-gamma-linolenic acid (DGLA, 20:3n-6), the other cyclooxygenase substrate and precursor of AA in PUFA biogenesis, shares the potentiating effect of AA although to a lesser extent (5). In the presence of 5 PM 12-HPETE. the 12lipoxygenase hydroperoxide product of AA, the oxygenation of EPA was also markedly enhanced and this enhancement was even higher than in the presence of 10pM AA. However, replacing 12-HPETE by 12HETE. the reduced lipoxygenase product, failed to exhibit any potentiation (6). This strongly suggests that AA potentiates EPA oxygenation through its lipoxygenasederived hydroperoxide. This kind of potentiation has also been observed with some other PUFA as substrates of platelet dioxygenases, particularly with DGLA. DHA and the mead acid (20:3n-9), although to a lesser degree (6. 7). In endothelial cells, EPA is a potential substrate of cyclooxygenase providing prostaglandin H, (PGH,)
24
Prostaglandins
Leukotrienes
and Essential Fatty Acids
which is also potentially transformed into PG13 by prostacyclin synthase. The formation of PGI, has been controversial when examined by incubating cells with EPA (8, 9). In the light of what we found in platelets, we investigated this with cultured human endothelial cells incubated with EPA in the presence of various amounts of AA, followed by gas chromatography-mass spectrometry detection of 6-keto-PGF,, and A17-6-ketothe stable metabolites of PGI? and PG13, PGF,,, respectively. In the absence of AA, 10 PM EPA was poorly transformed into PGI, with a production attaining 1 pmol/106 cells. When concentrations of AA progressively increased to 20 FM, PGI, formation was exponentially increased (10). A similar potentiation could be observed in the formation of PGE3 and Fjc(, suggesting that it occurred at the cyclooxygenase level rather than at the prostacyclin synthase one (10). Since endothelial cells possess a 15lipoxygenase activity, we replaced AA by various concentrations of 15-HPETE. Up to 2 FM, this hydroperoxide increased PGI, formation that plateaued over 20 FM (11) and was abolished at 200 FM, in agreement with the concept that high concentrations of hydroperoxides inhibit prostacyclin synthase (12). At low concentrations, the potentiating effect of 13-HPODE, the 15lipoxygenase product of linoleic acid (18:2n-6), was even more important, which is of relevance considering that animal 15-lipoxygenases prefer 18:2n-6 to AA as a substrate (13, 14). In contrast, when the reduced products I5-HETE and I3-HODE were used at the same concentrations, no potentiating effect could be observed (11). Finally, the oxygenation of adrenic acid (22:4n-6) into dihomoprostacyclin was also found markedly increased by 15-HPETE and 13HPODE (11).
INHIBITION
OF AA PEROXIDATION
min E before and after the intake, and surprisingly found that the level of the vitamin was significantly increased after EPA to attain that found in platelets from young adults (19). In both studies, no measurable accumulation of EPA or DHA could be detected after EPA supplementation in any plasma lipid class or platelet phospholipid class. In more recent experiments, this point has been investigated in using an in vitro approach. Normal platelets were treated with a moderate concentration of diamide to partially depress the reduced glutathione (GSH). 1 PM diamide decreased GSH by one-third, which subsequently decreased GSH-peroxidase by around one-third, and increased significantly platelet lipid peroxidation as measured by the basal production of malondialdehyde and of the cyclooxygenase and lipoxygenase end-products of AA (20). Such diamidetreated platelets were considered as a model simulating platelets from elderly people as far as the oxidative stress is concerned. This model was then used to investigate the effect of a low concentration of EPA. This concentration was chosen as unable to alter platelet vitamin E by itself and 100 nM was the concentration retained. When such a concentration of EPA was coincubated with diamide, whatever the addition sequence of the two molecules, platelet vitamin E and lipid peroxidation remain unaltered compared to control platelets but were significantly different from diamide-treated platelets (2 1). In the presence of EPA alone, the basal level of AA and the GSH-peroxidase activity, tested with a conventional method, were not altered. The hypothesis that could be then considered is that EPA might have decreased the cell peroxide tone (22), which could slow down the lipid peroxidation, in particular that of AA, as a result of a lower stimulation of 12-lipoxygenase by its own hydroperoxide product (23).
BY EPA
The inhibition by EPA of AA dioxygenation into prostanoids and leukotrienes has been well studied and reviewed (l), but has been observed with relatively high concentrations of substrates. This is the rationale for lowering the formation of AA metabolites after fish oil intake. However, the intake of relatively high amounts of fish oil may favor lipid peroxidation ( 15), which is rather unfortunate in subjects having a lower antioxidative defense. Elderly people, for instance, exhibit platelet hyperactivity associated with a lower platelet vitamin E content (16). In more recent investigations, we have found that such platelets have a lower glutathione peroxidase activity with a greater susceptibility to lipid peroxidation, especially that of AA (17). Providing low intake of purified EPA to these people (150 mg/day for 1 month or 100 mg/day for 2 months) induced a significant reduction of platelet aggregability whereas no change could be observed in a group who ingested the same amount of oleate as a placebo (18, 19). In the most recent of the two studies, we also measured platelet vita-
CONCLUSION The peroxide tone of the cell seems to have a crucial role in the relationships between AA and EPA oxygenated metabolisms. First considering our results obtained in both platelets and endothelial cells. it appears that the oxygenation of EPA into biologically active derivatives requires some peroxides which are adequately provided by the oxygenation of EPA. In addition to the well known antagonism of AA oxygenation by EPA. observed at relatively high concentrations of the substrates. it also appears in platelets that EPA may slow down the basal AA specific peroxidation (cycle- and lipooxygenation), then preventing the overconsumption of the cell vitamin E content. It is hard to hypothesize a mechanism for such a slowing down but we may speculate as it appears in the Figure, which summarizes the data, that EPA might counteract the basal lipoxygenation of AA, then preventing the relative accumulation of 12-HPETE. which is known as a stimulator of the
Interactions
Between Arachidonic
and Eicosapentaenoic
CO AA
APG?S
+ MDA
I
GSH-PX
MDA
PC& + 12.HEPE
12~tlETt;.
Figure Summary of some interactions between AA and EPA in platelets. The 12.peroxyl-AA radical (I 2-00”.AA) formed by the 12. lipoxygenase might in part be converted into l2-HPETE by using a hydrogen radical from vitamin E. which may also be used for the peroxidation chain breaking (conversion of R” and ROO” into RH and ROOH). A decreased GSH-peroxidase (GSH-PX) activity, as observed in aging or after partial GSH depletion, will increase the biological half-life of 12.HPETE which is known to stimulate its own production. This would result in the observed acceleration of the AA oxygenation cascade with an overconsumption of vitamin E (increased peroxide tone) and an increased formation of the oxygenation end-products (AA metabolites. MDA).In this scheme, EPA might slow down the cascade at the level of AA lipoxygenation. On the other hand. the scheme points out the potentiation of EPA oxygenation by I ZHPETE.
lipoxygenase. Altogether these data lead to a concept of unidirectional interactions between AA and EPA. AA promoting the specific oxygenation of EPA and EPA decreasing that of AA.
References I. 2.
3.
4.
5.
6
7
Leaf A. Weber PC. Cardiovascular effects of n-3 fatty acids. N Engl J Med 1988; 3 18: 549-557. Lagarde M. Metabolism of fatty acids by platelets and the functions of various metabolites in mediating platelet functions. Prog Lipid Res 1988: 27: 135-l 52. Lagarde M. Metabolism of n-3/n-6 fatty acids in blood and vascular cells. Biochem Sot Trans 1990; 18: 770-772. Needleman P. Raz A, Minkes MS, Ferrendelli JA, Sprecher H. Triene prostaglandins : prostacyclin and thromboxane bioxynthesis, a unique biological properties. Proc Natl Acad Sci USA 1979: 74:944-948. Boukhchache D, Lagarde M. Interactions between prostaglandin precursors during their oxygenation by human platelets. Biochim Biophys Acta 1982: 713: 3X6-392. Croset M. Lagarde M. Enhancement of eicosaenoic acid lipoxygenation in human platelets by l2-hydroperoxy derivative of arachidonic acid. Lipids 1985; 20:743-750. Croset M. Guichardant M, Lagarde M. Different metabolic behavior of long chain n-3 polyunsatured fatty acid\ in human platelets. Biochim Biophys Acta 1988:
Acids During Their Dioxygenase-dependent
Peroxidation
9611262-269. 8. Dyerberg J, Jorgensen KA. Amfred T. Human umbilical blood vessel converts all cis-5,8,1 I, 14.17. eicosapentaenoic acid to prostaglandin I,. Prostaglandins 1981: 22: 875-862. 9. Homstra G. Christ-Hazalhof E, Haddeman E. Ten Hoor F. Nugteren DH. Fish oil feeding lowers thromboxane and prostacyclin production by rat platelets and aorta and does not result in the formation of prostaplandin Ii. Prostaglandins 1981; 21:727-738. IO Bordet JC, Guichardant M. Lagarde M. Arachidonic acid strongly stimulates prostaglandin I, (PGI,) production from eicosapentaenoic acid in human endothelial cells. Biochem Biophys Res Commun 1986; 135:403~lO. II Bordet JC. Guichardant M. Lagarde M. Hydroperoxides produced by n-6 lipoxygenation of arachidonic and linoleic acids potentiate synthesis of prostacyclin related compounds. Biochim Biophys Acta 1988; 961:262-269. I2 Salmon JA, Smith DR. Flower RS, Moncada S. Vane JR. Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aortic microsomes. Biochim Biophys Acta 1978: 523:25&262. I3 Soberman RJ, Harper TW, Betteridge D, Lewis RA. Austen KF. Characterization and separation of the arachidonic acid 5-lipoxygenase and linoleic acid w-6 lipoxyenase (arachidonic acid l5-lipoxygenaae) of human polymophonuclear leukocytes. J Biol Chem I9XS: 760: 450845 15. 14. Buchanan MR. Haas TA, Lagarde M. Guichardant M. 13. hydroxyoctadecadienoic acid is the vessel wall chemorepellant factor. LOX. J Biol Chem 1985; 260: 1605&16059. 15. Harats D. Dabach Y. Hollander G. et al Fish oil ingestion in smohers and nonsmokers enchances peroxidation of plasma lipoproteins. Atherosclerosis I99 I : 90: 127-l 39. 16. VCricel E. Croset M, Sedivry P. Courpron P. Dechavanne M. Lagarde M. Platelets and aging. I-Aggregation. arachidonate metabolism and antioxidant status. Thromb Res 1988; 49:331-342. 17. V&ice1 E, Rey C. Calzada C, Haond P. Chapuy PH. Lagarde M. Age-related changes in arachidonic acid peroxidation and glutathion-peroxidase activity in human platelets. Prostaglandins 1992: 43:75-85 18. Driss F. V&ice1 E. Lagarde M, Dechavanne M, Darcet P. Inhibition of platelet aggregation and thromboxane synthesis after intake of small amount of ricosapentaneoic acid. Thromb Res 1984; 36:389-396. 19. Croset M, V&ice1 E. Rigaud M. et al Functions and tocopherol content of blood platelets from elderly people after low intake of purified eicosapentaenolc acid. Thromb Res 1990: 57: I-12. 20. Calsada C. VCricel E, Lagarde M. Decrease in platelel reduced glutathione increases lipoxygenase activity and decreases vitamin E. Lipids 1991: 26: 696-699. 21. Calzada C, V&-ice1 E. Lagarde M. Lower levels of lipid peroxidation in human platelets incubated with eicosapentaenoic acid. 22. Lands WEM. Kulmacz. RJ. The regulation of the biosynthesis of prostaglandins and leukotricnea. Prog Lipid Res 1986; 25: 105-l 09. 23 Siegel MI. MC Connel RT. Porter NA, Cuatrecasas P. Aspirin-lihe drugs interfere with arachidonate metabolism by inhibhion of the 12.hydroperoxy-5.8. IO. 11. eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proc Nat1 Acad Sci USA 1979: 76: 3773-3778.
25
Interactions Between Arachidonic and Eicosapentaenoic Acids During Their Dioxygenase-dependent Peroxidation M. Lagarde, E. Vericel, M. Croset. C. Calzada, J.C. Bordet* and M. Guichardant” INSERM U 352, Chirnie Biologique INSA de Lyon and *Lnboratoire France (Reprint requests to ML)
d’Ht%nobiologie,
FacultP A1e.vi.sCarrel, Lyon,
ABSTRACT. Eicosapentaenoic acid (EPA), a major polyunsaturated fatty acid of fish has been widely proposed as a potential nutrient for decreasing platelet-endothelial cell interactions and the subsequent atherogenesis and thrombogenesis. This is mainly based upon the decrease of arachidonic acid (AA) oxygenation into bioactive molecules like thromboxane A*. In addition, EPA may be oxygenated into its own active derivatives via cell dioxygenases. We report evidence for the requirement of specific peroxides, adequately provided by AA, to allow EPA to be oxygenated into its bioactive products like prostaglandin I,, a prostacyclin mimetic. On the other hand, we present some data that argue for a decreased basal AA dioxygenation (specific peroxidation) by small concentrations of EPA. The interactions between AA and EPA are then dual, EPA being able to counteract AA oxygenation whereas EPA requires AA to be efficiently oxygenated.
INTRODUCTION Arachidonic acid (AA, 20:4n-6) is the major polyunsatured fatty acid (PUFA) in animal tissues, except for limited areas in brain structures like the retina where the most abundant PUFA is docosahexaenoic acid (DHA, 22:6n-3). also called cervonic acid for this preferential location. Eicosapentaenoic acid (EPA, 20:5n-3) is found in low proportions in animal tissues, except when ingested in large amounts from marine oil or marine meat. In this case. it accumulates in most tissues together with DHA ingested in similar amounts from marine sources. The accumulation of EPA, following n-3 fatty acids, has been extensively studied, especially in blood and vascular cells where it is assumed to regulate AA metabolism Cl). The chemical structure of EPA resembles that of AA with only one additional double bond at carbon 17. This makes EPA a fairly good candidate for competing with the cell metabolism of AA. Indeed, EPA accumulates in cell glycerophospholipids mainly at the expense of AA and counteracts part of the specific oxygenation of AA via the cell dioxygenases, cyclooxygenase and lipoxygenases (2, 3). EPA has also the potential to be oxygenated into prostanoids and lipoxygenase products. In this paper, we present evidence for unidirectional interactions between AA and EPA. In platelets and endothelial cells. the specific oxygenation of EPA is markedly potentiated by AA via AA hydroperoxides whereas EPA may decrease the peroxidation of AA.
POTENTIATION AA
OF EPA OXYGENATION
BY
Although it is known that EPA may compete with the cyclooxygenation of AA in platelets and endothelial cells (4), presumably as a competitive inhibitor, the reverse is not true. When intact platelets are incubated with EPA alone, very few cyclooxygenase/thromboxane synthase products are formed, but those products appear when AA is coincubated with EPA (5). Dihomo-gamma-linolenic acid (DGLA, 20:3n-6), the other cyclooxygenase substrate and precursor of AA in PUFA biogenesis, shares the potentiating effect of AA although to a lesser extent (5). In the presence of 5 PM 12-HPETE. the 12lipoxygenase hydroperoxide product of AA, the oxygenation of EPA was also markedly enhanced and this enhancement was even higher than in the presence of 10pM AA. However, replacing 12-HPETE by 12HETE. the reduced lipoxygenase product, failed to exhibit any potentiation (6). This strongly suggests that AA potentiates EPA oxygenation through its lipoxygenasederived hydroperoxide. This kind of potentiation has also been observed with some other PUFA as substrates of platelet dioxygenases, particularly with DGLA. DHA and the mead acid (20:3n-9), although to a lesser degree (6. 7). In endothelial cells, EPA is a potential substrate of cyclooxygenase providing prostaglandin H, (PGH,)
24
Prostaglandins
Leukotrienes
and Essential Fatty Acids
which is also potentially transformed into PG13 by prostacyclin synthase. The formation of PGI, has been controversial when examined by incubating cells with EPA (8, 9). In the light of what we found in platelets, we investigated this with cultured human endothelial cells incubated with EPA in the presence of various amounts of AA, followed by gas chromatography-mass spectrometry detection of 6-keto-PGF,, and A17-6-ketothe stable metabolites of PGI? and PG13, PGF,,, respectively. In the absence of AA, 10 PM EPA was poorly transformed into PGI, with a production attaining 1 pmol/106 cells. When concentrations of AA progressively increased to 20 FM, PGI, formation was exponentially increased (10). A similar potentiation could be observed in the formation of PGE3 and Fjc(, suggesting that it occurred at the cyclooxygenase level rather than at the prostacyclin synthase one (10). Since endothelial cells possess a 15lipoxygenase activity, we replaced AA by various concentrations of 15-HPETE. Up to 2 FM, this hydroperoxide increased PGI, formation that plateaued over 20 FM (11) and was abolished at 200 FM, in agreement with the concept that high concentrations of hydroperoxides inhibit prostacyclin synthase (12). At low concentrations, the potentiating effect of 13-HPODE, the 15lipoxygenase product of linoleic acid (18:2n-6), was even more important, which is of relevance considering that animal 15-lipoxygenases prefer 18:2n-6 to AA as a substrate (13, 14). In contrast, when the reduced products I5-HETE and I3-HODE were used at the same concentrations, no potentiating effect could be observed (11). Finally, the oxygenation of adrenic acid (22:4n-6) into dihomoprostacyclin was also found markedly increased by 15-HPETE and 13HPODE (11).
INHIBITION
OF AA PEROXIDATION
min E before and after the intake, and surprisingly found that the level of the vitamin was significantly increased after EPA to attain that found in platelets from young adults (19). In both studies, no measurable accumulation of EPA or DHA could be detected after EPA supplementation in any plasma lipid class or platelet phospholipid class. In more recent experiments, this point has been investigated in using an in vitro approach. Normal platelets were treated with a moderate concentration of diamide to partially depress the reduced glutathione (GSH). 1 PM diamide decreased GSH by one-third, which subsequently decreased GSH-peroxidase by around one-third, and increased significantly platelet lipid peroxidation as measured by the basal production of malondialdehyde and of the cyclooxygenase and lipoxygenase end-products of AA (20). Such diamidetreated platelets were considered as a model simulating platelets from elderly people as far as the oxidative stress is concerned. This model was then used to investigate the effect of a low concentration of EPA. This concentration was chosen as unable to alter platelet vitamin E by itself and 100 nM was the concentration retained. When such a concentration of EPA was coincubated with diamide, whatever the addition sequence of the two molecules, platelet vitamin E and lipid peroxidation remain unaltered compared to control platelets but were significantly different from diamide-treated platelets (2 1). In the presence of EPA alone, the basal level of AA and the GSH-peroxidase activity, tested with a conventional method, were not altered. The hypothesis that could be then considered is that EPA might have decreased the cell peroxide tone (22), which could slow down the lipid peroxidation, in particular that of AA, as a result of a lower stimulation of 12-lipoxygenase by its own hydroperoxide product (23).
BY EPA
The inhibition by EPA of AA dioxygenation into prostanoids and leukotrienes has been well studied and reviewed (l), but has been observed with relatively high concentrations of substrates. This is the rationale for lowering the formation of AA metabolites after fish oil intake. However, the intake of relatively high amounts of fish oil may favor lipid peroxidation ( 15), which is rather unfortunate in subjects having a lower antioxidative defense. Elderly people, for instance, exhibit platelet hyperactivity associated with a lower platelet vitamin E content (16). In more recent investigations, we have found that such platelets have a lower glutathione peroxidase activity with a greater susceptibility to lipid peroxidation, especially that of AA (17). Providing low intake of purified EPA to these people (150 mg/day for 1 month or 100 mg/day for 2 months) induced a significant reduction of platelet aggregability whereas no change could be observed in a group who ingested the same amount of oleate as a placebo (18, 19). In the most recent of the two studies, we also measured platelet vita-
CONCLUSION The peroxide tone of the cell seems to have a crucial role in the relationships between AA and EPA oxygenated metabolisms. First considering our results obtained in both platelets and endothelial cells. it appears that the oxygenation of EPA into biologically active derivatives requires some peroxides which are adequately provided by the oxygenation of EPA. In addition to the well known antagonism of AA oxygenation by EPA. observed at relatively high concentrations of the substrates. it also appears in platelets that EPA may slow down the basal AA specific peroxidation (cycle- and lipooxygenation), then preventing the overconsumption of the cell vitamin E content. It is hard to hypothesize a mechanism for such a slowing down but we may speculate as it appears in the Figure, which summarizes the data, that EPA might counteract the basal lipoxygenation of AA, then preventing the relative accumulation of 12-HPETE. which is known as a stimulator of the
Interactions
Between Arachidonic
and Eicosapentaenoic
CO AA
APG?S
+ MDA
I
GSH-PX
MDA
PC& + 12.HEPE
12~tlETt;.
Figure Summary of some interactions between AA and EPA in platelets. The 12.peroxyl-AA radical (I 2-00”.AA) formed by the 12. lipoxygenase might in part be converted into l2-HPETE by using a hydrogen radical from vitamin E. which may also be used for the peroxidation chain breaking (conversion of R” and ROO” into RH and ROOH). A decreased GSH-peroxidase (GSH-PX) activity, as observed in aging or after partial GSH depletion, will increase the biological half-life of 12.HPETE which is known to stimulate its own production. This would result in the observed acceleration of the AA oxygenation cascade with an overconsumption of vitamin E (increased peroxide tone) and an increased formation of the oxygenation end-products (AA metabolites. MDA).In this scheme, EPA might slow down the cascade at the level of AA lipoxygenation. On the other hand. the scheme points out the potentiation of EPA oxygenation by I ZHPETE.
lipoxygenase. Altogether these data lead to a concept of unidirectional interactions between AA and EPA. AA promoting the specific oxygenation of EPA and EPA decreasing that of AA.
References I. 2.
3.
4.
5.
6
7
Leaf A. Weber PC. Cardiovascular effects of n-3 fatty acids. N Engl J Med 1988; 3 18: 549-557. Lagarde M. Metabolism of fatty acids by platelets and the functions of various metabolites in mediating platelet functions. Prog Lipid Res 1988: 27: 135-l 52. Lagarde M. Metabolism of n-3/n-6 fatty acids in blood and vascular cells. Biochem Sot Trans 1990; 18: 770-772. Needleman P. Raz A, Minkes MS, Ferrendelli JA, Sprecher H. Triene prostaglandins : prostacyclin and thromboxane bioxynthesis, a unique biological properties. Proc Natl Acad Sci USA 1979: 74:944-948. Boukhchache D, Lagarde M. Interactions between prostaglandin precursors during their oxygenation by human platelets. Biochim Biophys Acta 1982: 713: 3X6-392. Croset M. Lagarde M. Enhancement of eicosaenoic acid lipoxygenation in human platelets by l2-hydroperoxy derivative of arachidonic acid. Lipids 1985; 20:743-750. Croset M. Guichardant M, Lagarde M. Different metabolic behavior of long chain n-3 polyunsatured fatty acid\ in human platelets. Biochim Biophys Acta 1988:
Acids During Their Dioxygenase-dependent
Peroxidation
9611262-269. 8. Dyerberg J, Jorgensen KA. Amfred T. Human umbilical blood vessel converts all cis-5,8,1 I, 14.17. eicosapentaenoic acid to prostaglandin I,. Prostaglandins 1981: 22: 875-862. 9. Homstra G. Christ-Hazalhof E, Haddeman E. Ten Hoor F. Nugteren DH. Fish oil feeding lowers thromboxane and prostacyclin production by rat platelets and aorta and does not result in the formation of prostaplandin Ii. Prostaglandins 1981; 21:727-738. IO Bordet JC, Guichardant M. Lagarde M. Arachidonic acid strongly stimulates prostaglandin I, (PGI,) production from eicosapentaenoic acid in human endothelial cells. Biochem Biophys Res Commun 1986; 135:403~lO. II Bordet JC. Guichardant M. Lagarde M. Hydroperoxides produced by n-6 lipoxygenation of arachidonic and linoleic acids potentiate synthesis of prostacyclin related compounds. Biochim Biophys Acta 1988; 961:262-269. I2 Salmon JA, Smith DR. Flower RS, Moncada S. Vane JR. Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aortic microsomes. Biochim Biophys Acta 1978: 523:25&262. I3 Soberman RJ, Harper TW, Betteridge D, Lewis RA. Austen KF. Characterization and separation of the arachidonic acid 5-lipoxygenase and linoleic acid w-6 lipoxyenase (arachidonic acid l5-lipoxygenaae) of human polymophonuclear leukocytes. J Biol Chem I9XS: 760: 450845 15. 14. Buchanan MR. Haas TA, Lagarde M. Guichardant M. 13. hydroxyoctadecadienoic acid is the vessel wall chemorepellant factor. LOX. J Biol Chem 1985; 260: 1605&16059. 15. Harats D. Dabach Y. Hollander G. et al Fish oil ingestion in smohers and nonsmokers enchances peroxidation of plasma lipoproteins. Atherosclerosis I99 I : 90: 127-l 39. 16. VCricel E. Croset M, Sedivry P. Courpron P. Dechavanne M. Lagarde M. Platelets and aging. I-Aggregation. arachidonate metabolism and antioxidant status. Thromb Res 1988; 49:331-342. 17. V&ice1 E, Rey C. Calzada C, Haond P. Chapuy PH. Lagarde M. Age-related changes in arachidonic acid peroxidation and glutathion-peroxidase activity in human platelets. Prostaglandins 1992: 43:75-85 18. Driss F. V&ice1 E. Lagarde M, Dechavanne M, Darcet P. Inhibition of platelet aggregation and thromboxane synthesis after intake of small amount of ricosapentaneoic acid. Thromb Res 1984; 36:389-396. 19. Croset M, V&ice1 E. Rigaud M. et al Functions and tocopherol content of blood platelets from elderly people after low intake of purified eicosapentaenolc acid. Thromb Res 1990: 57: I-12. 20. Calsada C. VCricel E, Lagarde M. Decrease in platelel reduced glutathione increases lipoxygenase activity and decreases vitamin E. Lipids 1991: 26: 696-699. 21. Calzada C, V&-ice1 E. Lagarde M. Lower levels of lipid peroxidation in human platelets incubated with eicosapentaenoic acid. 22. Lands WEM. Kulmacz. RJ. The regulation of the biosynthesis of prostaglandins and leukotricnea. Prog Lipid Res 1986; 25: 105-l 09. 23 Siegel MI. MC Connel RT. Porter NA, Cuatrecasas P. Aspirin-lihe drugs interfere with arachidonate metabolism by inhibhion of the 12.hydroperoxy-5.8. IO. 11. eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proc Nat1 Acad Sci USA 1979: 76: 3773-3778.
25