Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets

Salari, Hassan; Braquet, P.; Borgeat, Pierre

doi:10.1016/0262-1746(84)90102-1

Cited by 248 publications

(96 citation statements)

References 18 publications

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“…Experiments with inhibitors of the metabolism of arachidonic acid were performed. Tiaprofenic acid is a potent inhibitor of cyclo-oxygenase (Schror et al, 1982) whereas ETYA is an inhibitor of the 12-and 15-lipoxygenases and of cyclo-oxygenase (Salari et al, 1984). At a concentration of 7 uM and at the cell concentration used, ETYA showed minimal (< 10%) inhibitory activity on the 5-lipoxygenase in PMNL (data not shown).…”

Section: Discussionmentioning

confidence: 91%

Thrombin‐activated platelets promote leukotriene B₄ synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Palmantier

Borgeat

1991

British J Pharmacology

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The addition of 2 × 108 human platelets to 8 × 106 polymorphonuclear leucocytes (PMNL) incubated in presence of 2.5 u ml−1 thrombin and 0.1 μm N‐formyl‐Met‐Leu‐Phe (FMLP) (or C5a or PAF) led to enhancement of leukotriene B4 (LTB4) synthesis by the PMNL (measured by h.p.l.c. as 20‐hydroxy‐ and 20‐carboxy‐LTB4) from 4 ± 1 pmol (in absence of platelets) to 26 ± 4 pmol (mean ± s.e.mean, n = 9). Platelets and thrombin were both essential for the enhancement of LTB4 synthesis. Platelets also caused enhancement of LTB4 synthesis from (30 ± 12 to 134 ± 25 pmol, n = 6) when PMNL pretreated with granulocyte‐macrophage colony‐stimulating factor were used in similar experiments. Enhancement of LTB4 synthesis was also observed (from 5 ± 1.5 to 26.5 ± 5 pmol, n = 9) when the supernatants of thrombin‐activated platelet suspensions were added to FMLP‐stimulated PMNL. Supernatants of platelet suspensions activated by thrombin in presence of cyclo‐oxygenase and 12‐lipoxygenase inhibitors led to greater enhancement (from 5 ± 3 to 153.5 ± 27.5 pmol, n = 3) of LTB4 synthesis by FMLP‐stimulated PMNL, suggesting that arachidonic acid itself, rather than its metabolites was responsible for the effects of platelets. Addition of arachidonic acid to FMLP‐stimulated PMNL at a concentration comparable to that measured in thrombin‐activated platelet supernatants (0.2 ± 0.025 μm, n = 6) mimicked the effect of platelets or platelet supernatants on LTB4 synthesis in FMLP‐activated PMNL. The present data indicate that under conditions of cell activation by physiological agonists, platelets can significantly increase the formation of the proinflammatory compound LTB4 in PMNL by providing arachidonic acid. These data lend support to the concept that platelet‐PMNL interactions could modulate the inflammatory process.

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Section: Discussionmentioning

confidence: 91%

Thrombin‐activated platelets promote leukotriene B₄ synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Palmantier

Borgeat

1991

British J Pharmacology

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“…Due to our own experiments (data not shown), a competitive action of NDGA up to 100 M is excluded. Salari et al (40) investigated the action of NDGA on the generation of lipoxygenase products in a whole cell system. After 20 min, the metabolites were detected by HPLC.…”

Section: Discussionmentioning

confidence: 99%

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Sauvant¹,

Holzinger²,

Gekle³

2002

Journal of the American Society of Nephrology

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Abstract. The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases, mitogenactivated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [ 14 C]PAH was abolished by the phospholipase A 2 inhibitor AACOCF3. [ 14 C]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA 2 . In addition, EGF stimulated the influx of extracellular Ca 2ϩ . However, Ca 2ϩ -influx was not required for the stimulatory action of EGF on [ 14 C]PAH uptake. Inhibitors of COX and lipoxygenases reduced [ 14 C]PAH uptake dosedependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [ 14 C]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E 2 (PGE 2 ) increased basolateral [ 14 C]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [ 14 C]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [ 14 C]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA 2 , leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.The organic anion transport system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds (1). This system consists of a basolaterally located organic anion exchanger and a less well characterized transport step at the apical membrane (2).The basolateral organic anion exchanger is a tertiary active transport system, dependent on an inward-directed Na ϩ -gradient to drive the uptake of ␣-ketoglutarate, which is then exchanged for organic anions (1-4). The basolateral exchanger for organic anions and dicarboxylates was cloned by three independent groups (5-7) in 1997 and named OAT1 (rat), ROAT1 (rat), or fROAT1 (winter flounder). The homologous protein was cloned from human kidney only recently and wa...

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“…Polyacetylenes as arachidonic acid mimetics Short after the discovery of the 5-LO enzyme, various AA derivatives, in particular those with acetylene moieties such as 5,8,11,14-eicosatetraynoic acid (ETYA) [65] and 5,8,11-eicosatriynoic acid [188], but also 15-hydro(pero)xy-5,8,11,13-eicosatetraenoic acid (15-H(P)ETE) [189,190], 5,12-diHETE, or LT-analogues like 5,6-methano-LTA 4 [191], [192] were found to inhibit 5-LO activity. Moreover, AA-861 1 [2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone, see above] contains two acetylene moieties in addition to the redox-active 1,4-benzoquinone structure [67].…”

Section: Alkaloidsmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

153

135

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets

Cited by 248 publications

References 18 publications

Thrombin‐activated platelets promote leukotriene B₄ synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Thrombin‐activated platelets promote leukotriene B₄ synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

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Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets

Cited by 248 publications

References 18 publications

Thrombin‐activated platelets promote leukotriene B4 synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Thrombin‐activated platelets promote leukotriene B4 synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

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Thrombin‐activated platelets promote leukotriene B₄ synthesis in polymorphonuclear leucocytes stimulated by physiological agonists

Thrombin‐activated platelets promote leukotriene B₄ synthesis in polymorphonuclear leucocytes stimulated by physiological agonists