Leukotriene-lipoxygenase pathway and drug discovery.

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  • ABE Masayoshi
    Department of Pharmacology, School of Medicine, Fukuoka University
  • YOSHIMOTO Tanihiro
    Department of Molecular Pharmacology, Kanazawa University Graduate School of Medical Science

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  • ロイコトリエン・リポキシゲナーゼ代謝系と創薬
  • ロイコトリエン リポキシゲナーゼ タイシャケイ ト ソウヤク

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Abstract

The first drugs affecting the leukotriene-lipoxygenase pathway, which have been introduced in clinical application, inhibit effects of slow reacting substance of anaphylaxis (SRS-A). Although, a 5-lipoxygenase inhibitor was first used in clinical practice as an anti-asthma drug, cysteinyl-leukotriene type 1 receptor (cysLT1R) antagonists are preferred as anti-asthma and anti-rhinitis drugs because they are almost as effective as the 5-lipoxygenase inhibitors but have fewer side effects. The cloning of genes related to lipoxygenase-leukotriene metabolism prompted us to try to elucidate the role of leukotrienes in various inflammations. There are at least two types of cysLTRs known: cysLT1R and cysLT2R. CysLT1R plays an important role in the pathophysiology of asthma; however, the role of the cysLT2R remains unknown. The abundant distribution of cysLT2R in heart and brain tissues suggests that cysLTs play an important role in the pathophysiology of ischemic heart diseases or arrhythmias and through this receptor (cysLT2R), psychoneurological disorders. The use of a selective cysLT2R antagonist may clarify these questions. Since the 5-lipoxygenase pathway is abundantly expressed in atherosclerotic lesions, and 12/15-lipoxygenase is able to oxygenate polyunsaturated fatty acid esterified in the membranous phospholipids, 5-lipoxygenase or 12/15-lipoxygenase inhibitors may prevent progression of atherosclerosis. In addition, it has been reported that 15-lipoxygenase participates in suppression of prostate cancer. In conclusion, the leukotriene-lipoxygenase metabolism may be involved in the pathophysiology of acute inflammatory to chronic progressive disorders. We think that more drugs modifying leukotriene-lipoxygenase metabolism will be introduced into clinical practice in the future.<br>

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