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

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 structure-activity relationships are discussed. Abbreviations AA:arachidonic acid CLP:coactosine-like potein COX:cyclooxygenase GPCR:G protein-coupled receptor GPX:glutathione peroxidase GSH:glutathione FLAP:5-lipoxygenase-activating protein H(P)ETE:hydro(pero)xyeicosatetraenoic acid iNOS:inducible nitric oxide synthase LO:lipoxygenase LOOH:lipid hydroperoxide LT:leukotriene MAPEG:membrane-associated proteins in eicosanoid and glutathione metabolism MAPK:mitogen-activated protein kinase NDGA:nordihydroguaiaretic acid NFκB:nuclear factor κB PAF:platelet-activating factor fMLP: N -formyl-methionyl-leucyl-phenylalanine PC:phosphatidylcholine PL:phospholipase PK:protein kinase PMNL:polymorphonuclear leukocytes PT:pentacylic triterpene SAR:structure-activity relationships