Associate editor: C.E. Müller
Therapeutic options for 5-lipoxygenase inhibitors

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Abstract

5-Lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid (AA) into leukotriene (LT) A4 and 5-hydroperoxyeicosatetraenoic acid. LTA4 can then be converted into LTB4 by LTA4 hydrolase or into LTC4 by LTC4 synthase and the LTC4 synthase isoenzymes MGST2 and MGST3. LTB4 is a potent chemoattractant for neutrophils, eosinophils and monocytes leading to adherence of phagocytes to vessel walls, neutrophil degranulation and release of superoxide anions. LTC4 and its metabolite, LTD4, are potent bronchoconstrictors that increase vascular permeability and stimulate mucus secretion from airways. Recent data also suggest that LT have an immunomodulatory role. Due to these properties, the increased biosynthesis of LT in asthma, and based upon clinical data obtained with CysLT1 receptor antagonists in asthma patients, there is a consensus that CysLT play a prominent role in asthma. In this review, we summarize the knowledge on possible functions of the 5-LO pathway in various diseases like asthma, cancer and cardiovascular events and review the corresponding potential therapeutic roles of 5-LO inhibitors.

Introduction

The arachidonic acid (AA) transforming enzyme 5-lipoxygenase (5-LO) catalyzes the conversion of AA into 5(S)-hydroperoxyeicosatetraenoic acid (5-HPETE) and leukotriene (LT) A4 (Fig. 1) (Samuelsson et al., 1987, Funk, 2001). The unstable intermediate LTA4 can be further converted into LTB4 by LTA4 hydrolase (Haeggström, 2004) or into LTC4 by LTC4 synthase and the LTC4 synthase isoenzymes MGST2 or murine MGST3 (Schröder et al., 2003). LTB4 is a potent chemoattractant for neutrophils, eosinophils and monocytes leading to adherence of phagocytes to vessel walls, neutrophil degranulation and release of superoxide anions. LTC4 and its metabolite, LTD4, are potent bronchoconstrictors that increase vascular permeability and stimulate mucus secretion from airways. Based on these properties, together with increased biosynthesis of LT in asthma and due to clinical data obtained with CysLT1 receptor antagonists in asthma patients, there is a consensus that CysLT play a prominent role in asthma. In this review, we summarize the knowledge on possible functions of the 5-LO pathway in various diseases and the corresponding potential therapeutic roles of 5-LO inhibitors.

Section snippets

Enzymology of the 5-lipoxygenase pathway

LT are bioactive lipid mediators produced and released from activated leukocytes, mediating their effects via specific G protein-coupled receptors (GPCR). The initial step in the biosynthesis of LT is the conversion of liberated AA by the 5-LO (for review, see Werz, 2002). This soluble dioxygenase incorporates molecular oxygen at position C5 of the fatty acid, yielding 5-HPETE that is further metabolized by 5-LO to the instable epoxide LTA4 (Fig. 1). The fate of LTA4 depends on the cell type

Regulation of cellular 5-lipoxygenase activity

LT display a great variety of biological effects. Thus, it is not surprising that both 5-LO expression and cellular LT biosynthesis are tightly regulated (Steinhilber, 1994). Cellular formation of 5-LO metabolites is controlled by the liberation of AA which is mainly catalyzed by cytosolic phospholipase A2 (cPLA2) as well as by the regulation of 5-LO activity. In contrast to Ca2+-ionophore A23187, naturally occurring inflammatory mediators like N-formyl-methionyl-leucyl-phenylalanine (fMLP),

BLT receptors

The biological actions of LT are mediated by specific receptors on the surface of their target cells. LTB4 exerts its effects via binding to the BLT1 and BLT2 receptors, which are GPCR with high homology (36–45%), but with distinct tissue distribution and distinct pharmacological properties (for review, see Brink et al., 2003). The BLT1 receptor is a high affinity receptor specific for LTB4 and is prominently expressed in leukocytes and present in much lower amounts in spleen, thymus, bone

Molecular pharmacology of 5-lipoxygenase inhibitors

Based on the pathophysiological implications of 5-LO products and the potential benefit of an anti-LT therapy, strong efforts have been made within the past 20 years in order to develop selective and potent pharmacological agents that intervene with LT. In this respect, 2 different strategies have been pursued: (I) inhibition of the biosynthesis of LT and (II) inhibition of the action of LT.

To achieve reduction of LT formation, reasonable targets include PLA2 enzymes, 5-LO, FLAP, LTA4 hydrolase

5-Lipoxygenase pathway and diseases

LT have been identified as mediators of a variety of inflammatory and allergic reactions including rheumatoid arthritis, inflammatory bowel disease, psoriasis, allergic rhinitis but their major pathophysiological implication was linked to bronchial asthma (Samuelsson et al., 1987, Lewis et al., 1990). Recently, the 5-LO pathway has also been associated with atherosclerosis, osteoporosis and certain types of cancer like prostate cancer (see below). Thus, in addition to the classical indications

Acknowledgments

Studies of the authors are supported by the EU (LSHM-CT-2004-005033) and Deutsche Forschungsgemeinschaft (GRK 757).

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