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 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.

Anti-Inflammatory Activity of Vitex leucoxylon L. Bark Extracts Against Freund's Complete Adjuvant Induced Arthritis in Sprague Dawley Rat

“…The polyphenol, nordihydroguaretic acid (NDGA) from the Mexican desert plant Larrea divaricata was the first plant-derived 5-Lipoxygenase inhibitor [20] . Plant derived chemical constituents like flavanoids, coumarins, Quinones, pentacyclic triterpenes, sesquiterpenes, alkaloids and polyacetylates have been reported to be 5-Lipoxygenase inhibitors [21,22] . In the present study, VL-89/185A from barks of V. leucoxylon showed 5-lipoxygenase inhibitory activity.…”

“…There has been some concern over the use of COX-2 inhibitors for therapeutic intervention, especially since some of the products based on COX-2 were either withdrawn or made to carry warning by the US FDA [8,9] . 5-Lipoxygenase (5-LOX) inhibitors of herbal origin on the other hand are reported to offer significant relief and devoid of adverse effects 5-LOX inhibitors are thus becoming first choice of treatment for chronic inflammatory disease such as arthritis [10,11] . Tumor necrosis factor α (TNF-α) is a pleotropic inflammatory cytokine produced by the immune system that suppresses tumor cell proliferation.…”

Anti-inflammatory potential of 2-styrylchromones regarding their interference with arachidonic acid metabolic pathways

“…Catalytically active 5-LOX requires the conversion of Fe(II) to Fe(III), conferred by certain lipid hydroperoxides (LOOH). Most 5-LOX inhibitors act at the catalytic domain by reducing or chelating the active-site iron or by scavenging radical intermediates in the redox cycle of the iron [6,25]. Accordingly, the reduction of ferric ion is a possible mechanism of inhibition of LTB 4 production by 2-SC, since the most effective compounds (1A-1D) also behaved as strong reducers (Fig.…”

“…The anti-inflammatory potential of 2-styrylchromones, concerning their interference with the arachidonic acid metabolic pathways, has not been explored so far. However, this may represent a promising field of research considering the potent inhibition of eicosanoids production by certain flavonoids containing structural similarities with 2-SC (see [25] for review). Therefore, the purpose of this work was to evaluate the inhibition of COX-1 and COX-2 activities, in a cell-free system, as well as the inhibition of LTB 4 production, in human PMNL, by a group of 2-SC (Fig.…”

Atividade anti-inflamatória e caracterização fitoquímica do chá e de diferentes extratos de Tithonia diversifolia (Asteraceae)

“…Dados da literatura mostram que moléculas de origem vegetal apresentam importantes atividades anti-inflamatórias e que muitas de suas ações são relacionadas à habilidade de inibir a síntese ou ação de citocinas, quimiocinas e moléculas de adesão, vias do ácido araquidônico e NO, além da inibição do NF-κB (Calixto et al, 2004;Werz, 2007).…”