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

Abstract

The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA₄ by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA₄ yields LTB₄ and the cysteinyl-LTs C₄, D₄ and E₄. 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

Key words

5-Lipoxygenase - arachidonic acid - leukotrienes - leukocytes - inflammation - plants - natural compounds - inhibitors

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