The biologically active leukotrienes. Biosynthesis, metabolism, receptors, functions, and pharmacology.

Lewis, Robert A.; Austen, K. Frank

doi:10.1172/jci111312

Cited by 618 publications

(151 citation statements)

References 101 publications

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“…Interestingly, the I& for inhibition of ["51]L-739,059 binding to FLAP by arachidonic acid (10-20 PM) is similar to the K,,, for arachidonic acid determined for 5-LO from porcine [25] and human [26] leukocytes. The demonstration that FLAP specifically binds arachidonic acid suggests that FLAP may activate 5-LO by binding and transferring this substrate to the enzyme for the concerted synthesis of LTA,.…”

Section: Discussionsupporting

confidence: 59%

5‐lipoxygenase‐activating protein is an arachidonate binding protein

Mancini¹,

Abramovitz²,

Cox³

et al. 1993

FEBS Letters

202

124

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5-Lipoxygenase-activating protein (FLAP) is an 1 S-kDa integral membrane protein which is essential for cellular leukotriene (LT) synthesis, and is the target of LT biosynthesis inhibitors. However, the mechanism by which FLAP activates S-LO has not been determined. We have expressed high levels of human FLAP in Spodopteru frugiperda (39) insect cells infected with recombinant baculovirus, and used this system to demonstrate that FLAP specifically binds ['2sI]L-739,059, a novel photoaffinity analog of arachidonic acid. This binding is inhibited by both arachidonic acid and MK-886, an LT biosynthesis inhibitor which specifically interacts with FLAP. These studies suggest that FLAP may activate 5-LO by specifically binding arachidonic acid and transferring this substrate to the enzyme.5-Lipoxygenase-activating protein; 5-Lipoxygenase; Arachidonic acid; Photoaffinity labeling; Baculovirus

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Section: Discussionsupporting

confidence: 59%

5‐lipoxygenase‐activating protein is an arachidonate binding protein

Mancini¹,

Abramovitz²,

Cox³

et al. 1993

FEBS Letters

202

124

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“…One of the important reactions catalyzed by lipoxygenase is the production of leukotriene from arachidonic acid for the initiation of a series of inflammatory physiological and pathological processes. 39) Our results show that the tyrosinase inhibitory activity of HP is far stronger than that of the other hawthorn fruit extracts, suggest that the active phenolics were concentrated by ethyl acetate extraction. In terms of lipoxygenase inhibitory activity, all of the reference compounds and extracts, such as HP and HF, showed similar levels (IC 50 values of approximately 100 mg/ml).…”

Section: Antioxidant Activities Of Hawthorn Extracts and Related Compmentioning

confidence: 63%

Polyphenolic Content and Physiological Activities of Chinese Hawthorn Extracts

Cui

Nakamura

Tian

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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Hawthorn polyphenol (HP) was prepared by ethyl acetate treatment of the ethanol extract (HE) of Chinese hawthorn fruit. The concentrations of 15 polyphenols in the HP, HE, extraction residue (HJ), and a hawthorn leaf extract (HF) were determined by HPLC. For HP, the total content of the 15 polyphenols was 21.4%, comprised of 19.7% of procyanidins, 1.21% of chlorogenic acid, and 0.48% of flavonoids, compared to 2.55% for the HE. The yields of procyanidin monomer, dimer, trimer, tetramer, and pentamer were 50.5%, 30.3%, 23.0%, 14.6%, and 12.5% respectively, and the mean degree of polymerization was reduced to 1.39 (HP) from 1.65 (HE). Seven different physiological actions of the four extracts were investigated. The HP showed strong O 2 À and OH scavenging capacities (IC 50 values of 6.3 g/ml and 1.1 g/ml respectively), as well as selective prolyl endopeptidase inhibition (IC 50 of 60 g/ml). The active constituents appeared to be procyanidins.Key words: Crataegus pinnatifida; HPLC; procyanidin; antioxidant; free radicalsIn Europe, standardized extracts of the leaves and flowers of Crataegus oxyacantha and Crataegus monogyna are used in the therapy for moderate (NYHA II) congestive heart failure. 1,2) These extracts exert several pharmacological and clinical effects, such as antiischemia/reperfusion-injury, anti-arrhythmic, hypolipidemic, and hypotensive effects. 1,2) Flavonoids and procyanidins are considered to be the two main active constituents. 2) Species of Chinese hawthorn, particularly Crataegus pinnatifida and Crataegus pinnatifida Bge. var. major NE Br., have also been used as herbal medicines. 2,3) Studies indicate that Chinese hawthorn extracts have beneficial effects, such as antioxidant, 4,5) anti-inflammatory, 6) and hypolipidemic effects, 7) as well as protective effects on the brain and vascular endothelium 8,9) and endothelium-dependent relaxation. 10) Recently, we analyzed 37 major cultivars of Chinese hawthorn using high performance liquid chromatography (HPLC), and found that procyanidins, which were present in high concentrations, were the main phenolic active constituents in these fruits. 11) In general, the hawthorn found in China is an edible fruit that is popular for its special acidic taste. It is bigger than its European counterpart. Since the content of organic acid in Chinese hawthorn fruits can be up to 5% (fresh weight), they are used to produce various foods, such as jams, jellies, juices, tinned foods, wines, and various sweet foods. However, the high sugar content of these fruits counteracts the benefits of polyphenols for consumers of advanced age or for those who suffer from hypertension, cardiovascular disease, or diabetes. Hence, it is desirable to separate the polyphenol and sugar components. Previously, hawthorn extract (HE) for medical applications were ethanol-extracted from the dried fruit of the Chinese hawthorn. 12) These crude extracts contain many undesirable substances, such as carbohydrates, organic acids, and moisture, which not only reduce the concentration of acti...

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“…Arachidonic acid oxidation catalyzed by 5-1ipoxygenase (5-LO; EC 1.13.11.34) activity leads to the formation of potent, biologically active molecules such as leukotriene B4 (LTB4), and cysteinyl leukotrienes, namely leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4) [1,2]. While a great deal of evidence from basic biochemical studies has focused on cells that possess 5-LO enzyme, it is now clear that the formation of leukotrienes is not strictly limited to those cells that have these primary oxidative enzymes.…”

Section: Introductionmentioning

confidence: 99%

Leukotriene A₄, and not leukotriene B₄, is the main 5‐lipoxygenase metabolite released by bovine leukocytes

1996

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The production of leukotriene A4 (LTA4)-derived metabolites, analysed by RP-HPLC, was studied in purified bovine polymorphonuclear leukocyte (PMNL) preparations and in PMNL-platelet coincubations after challenge with the calcium ionophore A23187. The results obtained show that in bovine PMNL LTB4 represents the main LTA4 metabolite. When washed platelets were added to PMNL, LTC4 was the main enzymatic metabolite observed, indicating a substantial transfer of PMNL-derived LTA4 to platelets. The synthesis of LTC4 was accompanied by a significant decrease in LTB4, suggesting that a quota of the LTB4 synthesized in PMNL preparations is the result of transcellular metabolism of released LTA4 by neighbouring PMNL. Reduction of PMNL-PMNL interactions through dilution of cell incubates allowed us to estimate that most of the leukotriene A4 synthesized by PMNL is indeed released from the cell. LTA4, and not LTB4, represents the main 5-1ipoxygenase metabolite released by bovine PMNL.

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The biologically active leukotrienes. Biosynthesis, metabolism, receptors, functions, and pharmacology.

Cited by 618 publications

References 101 publications

5‐lipoxygenase‐activating protein is an arachidonate binding protein

5‐lipoxygenase‐activating protein is an arachidonate binding protein

Polyphenolic Content and Physiological Activities of Chinese Hawthorn Extracts

Leukotriene A₄, and not leukotriene B₄, is the main 5‐lipoxygenase metabolite released by bovine leukocytes

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The biologically active leukotrienes. Biosynthesis, metabolism, receptors, functions, and pharmacology.

Cited by 618 publications

References 101 publications

5‐lipoxygenase‐activating protein is an arachidonate binding protein

5‐lipoxygenase‐activating protein is an arachidonate binding protein

Polyphenolic Content and Physiological Activities of Chinese Hawthorn Extracts

Leukotriene A4, and not leukotriene B4, is the main 5‐lipoxygenase metabolite released by bovine leukocytes

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Leukotriene A₄, and not leukotriene B₄, is the main 5‐lipoxygenase metabolite released by bovine leukocytes