Inhibition of 5-Lipoxygenase Product Synthesis by Oliver Werz Natural Compounds of Plant Origin Review Abstract Abbreviations AA: arachidonic acid The biosynthesis of leukotrienes (LTs) is initiated by the transfor- CLP: coactosine-like potein mation of free arachidonic acid to LTA4 by 5-lipoxygenase (5-LO). COX: cyclooxygenase Subsequent enzymatic conversion of LTA4 yields LTB4 and the cy- GPCR: G protein-coupled receptor steinyl-LTs C4,D4 and E4. LTs have prominent functions in patho- GPX: glutathione peroxidase physiology and are connected to numerous disorders including GSH: glutathione bronchial asthma, allergic rhinitis, inflammatory bowel and skin FLAP: 5-lipoxygenase-activating protein diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovas- H(P)ETE: hydro(pero)xyeicosatetraenoic acid cular diseases. Pharmacological and genetic interruption of the 5- iNOS: inducible nitric oxide synthase LO pathway or blockade of LT receptors, serving as means for inter- LO: lipoxygenase vention with LTs, may be of therapeutic value for certain related LOOH: lipid hydroperoxide disorders. Natural or plant-derived substances were among the LT: leukotriene first 5-LO inhibitors identified in the early 1980 s. To date, a huge MAPEG: membrane-associated proteins in eicosanoid and number of diverse plant-derived compounds have been reported glutathione metabolism to interfere with 5-LO product synthesis. However, many investi- MAPK: mitogen-activated protein kinase 1331 gations have addressed the efficacy of a given compound solely in NDGA: nordihydroguaiaretic acid cellular test systems and analysis of direct interference with 5-LO NFkB: nuclear factor kB has been neglected. In the first part of this review, the biology and PAF: platelet-activating factor molecular pharmacology of the 5-LO pathway is summarized in fMLP: N-formyl-methionyl-leucyl-phenylalanine order to understand its overall regulation and complexity as well PC: phosphatidylcholine as to comprehend the possible points of attack of compounds that PL: phospholipase eventually lead to inhibition of 5-LO product formation in intact PK: protein kinase cells. In the second part, natural compounds that interfere with PMNL: polymorphonuclear leukocytes 5-LO product formation are compiled and grouped into structural PT: pentacylic triterpene classes, and the underlying molecular mechanisms and structure- SAR: structure-activity relationships activity relationships are discussed. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Key words 5-Lipoxygenase ´ arachidonic acid ´ leukotrienes ´ leukocytes ´ in- flammation ´ plants ´ natural compounds ´ inhibitors Affiliation Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tuebingen, Tuebingen, Germany Correspondence Prof. Dr. Oliver Werz ´ Department of Pharmaceutical Analytics ´ Pharmaceutical Institute ´ Eberhard-Karls-University Tuebingen ´ Auf der Morgenstelle 8 ´ 72076 Tuebingen ´ Germany ´ Phone: +49-7071-297-8793 ´ Fax: +49-7071-294-565 ´ E-mail: [email protected] Received August 14, 2007 ´ Revised September 3, 2007 ´ Accepted September 8, 2007 Bibliography Planta Med 2007; 73: 1331±1357 Georg Thieme Verlag KG Stuttgart ´ New York DOI 10.1055/s-2007-990242 ´ Published online October 16, 2007 ISSN 0032-0943 The Leukotriene Synthetic Pathway cy at the CysLT2 receptor and LTE4 is a weak agonist [6]. The CysLT1 receptor is expressed in eosinophils, monocytes, macro- Leukotrienes (LTs) are bioactive lipid mediators mainly produced phages, and bronchial smooth muscle cells whereas the CysLT2 and released from activated leukocytes [1]. The initial step in LT receptor is expressed more ubiquitously. CysLT1 receptor med- biosynthesis is the dioxygenation of free arachidonic acid (AA) by iates vascular leakage, bronchoconstriction, dendritic cell ma- 5-lipopxygenase (5-LO), yielding 5(S)-hydroperoxyeicosatetrae- turation and migration, but both receptors contribute to macro- noic acid (5-HPETE) that is further metabolized by 5-LO to the in- phage activation, smooth muscle proliferation and fibrosis. The stable epoxide LTA4 (Fig.1, for review see [2]). In neutrophils and CysLTR antagonists pranlukast, montelukast, zafirlukast, acting monocytes, LTA4 can be converted to LTB4 by LTA4 hydrolase, primarily on CysLT1, have been shown to be clinically efficacious whereas in mast cells and eosinophils, LTC4 synthase or mem- in chronic asthma and have been successfully introduced into brane-associated proteins in eicosanoid and glutathione metab- market [7]. The CysLT2 receptor is insensitive to these antago- olism (MAPEGs) can conjugate LTA4 with glutathione (GSH), nists and the therapeutic potential of this receptor is unclear. yielding the cysteinyl-LT (Cys-LT)C4 that can be cleaved in the Review extracellular environment yielding LTD4 and then LTE4 (Fig.1). LTB4 binds BLT1 and BLT2 receptors, which show high homology Alternatively, de novo synthesized LTA4 can be transferred to (36±45%), but quite distinct tissue distribution and distinct neighbouring cells that are unable to produce LTA4 itself but ex- pharmacological properties (for review, see [6]). The BLT1 recep- press LTA4 hydrolase or LTC4 synthase/MAPEGs (e.g., parenchy- tor is prominently expressed in leukocytes, possesses high affi- mal cells or erythrocytes), allowing subsequent generation of nity (Kd = 0.39 nM) and specificity for LTB4, and is coupled to Gi LTB4 or LTC4, respectively [3]. Finally, when 5-LO and 12-LO or and Gq proteins [8]. BLT1 mediates typical effects of LTB4 includ- 15-LO act together, lipoxins (LXs) might be formed, that are ing chemotaxis, formation of superoxide, release of lysosomal bioactive trihydroxytetraene-containing lipid mediators func- enzymes and leukocyte adhesion to endothelial cells. The BLT1 tioning as stop signals for inflammatory responses [4]. seems to be related to atherogenesis, bronchial asthma, glomer- ulonephritis, arthritis and chronic inflammatory bowel diseases (for review see [9]). The more widely expressed BLT2 binds LTB4 Biological Effects of Leukotrienes with a 20-fold lower affinity as BLT1 and the physiological and pathophysiological roles of the BLT2 are hardly understood. LTB4 is a potent chemoattractant for leukocytes causing adher- ence of phagocytes to vessel walls, neutrophil degranulation Finally, a Gi-coupled GPCR specific for 5-oxo-ETE (formed by oxi- and release of superoxide anions, whereas cysLTs are potent dation of 5-HETE) may exist in eosinophils, neutrophils and bronchoconstrictors increasing vascular permeability and stim- monocytes [10]. 5-Oxo-ETE is a chemoattractant for leukocytes ulating mucus secretion from airways [5]. These biological ac- and induces actin polymerization, Ca2+ mobilization, integrin ex- tions of LTs are mediated by specific Gprotein-coupled receptors pression and degranulation, stimulates the proliferation of pros- 1332 (GPCRs) on the surface of their target cells. The CysLTs bind to tate cancer cells [11], and may play a role in allergic asthma [12]. CysLT1 and CysLT2 receptors that signal via Gq proteins (for re- view, see [6]). For the CysLT1 receptor the agonist potency is LTD4 >> LTC4 >LTE4, whereas LTC4 and LTD4 exhibit similar poten- 5-LO and Diseases Initially, LTs have been identified as the chemical nature of the slow-reacting substance of anaphylaxis (SRSA) that induced a pronounced contraction of smooth muscles in a slow mode, and it soon became clear that LTs play important roles in inflamma- tory and allergic disorders. Therefore, bronchial asthma, allergic rhinitis, inflammatory skin diseases, rheumatoid arthritis, in- flammatory bowel diseases, have long been accounted as 5-LO- mediated or -associated (for review see [13]). Today, it is general- ly agreed that bronchial asthma is the major 5-LO-associated dis- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ease and, in fact, the available anti-LT therapy is approved for treatment of asthma only. On the other hand, LTs play a minor role in the pathophysiology of inflammatory bowel diseases and rheumatoid arthritis in humans. Similarly, the rather disappoint- ing results of anti-LT drugs in psoriasis led to the conclusion that the 5-LO pathway is negligible in this disease. Novel technologies in molecular biology and cell biology, mainly attributable to the elucidation of the receptors of LTs, genotyping approaches, and cumulating data from 5-LO knock-out mice led to deeper insights into the pathophysiology of 5-LO and its pro- ducts in recent years. Accordingly, there are indications for novel Fig. 1 Conversion of arachidonic acid by 5-lipoxygenase. LT = leuko- disorders related to 5-LO products including osteoporosis [14], triene; 5-H(P)ETE = 5-hydro(pero)xyeicosatetraenoic acid. [15], cancer (i.e., prostate, pancreas and breast) [16], [17], [18], Werz O. Inhibition of 5-Lipoxygenase ¼ Planta Med 2007; 73: 1331±1357 and cardiovascular diseases including atherosclerosis, heart at- brane, mediated by tryptophan residues (Trp-13, -75, and -102) tack and stroke [19], [20]. Clinical trials will reveal if anti-LT ther- in conjunction with Ca2+ [30], [32], and this process seemingly is apy is valuable for the treatment of these disorders. essential for cellular 5-LO product synthesis. It is conceivable that (preferrably lipophilic) compounds may interrupt such 5- LO membrane association (5-LO translocation inhibitors), there- Expression and Structure of