title: On the inhibition of 5-lipoxygenase product formation by tryptanthrin: mechanistic studies and efficacy in vivo.
abstract: OBJECTIVE
  Leukotrienes (LTs) are pro-inflammatory mediators produced by 5-lipoxygenase (5-LO). Currently available 5-LO inhibitors either lack efficacy or are toxic and novel approaches are required to establish a successful anti-LT therapy. Here we provide a detailed evaluation of the effectiveness of the plant-derived alkaloid tryptanthrin as an inhibitor of LT biosynthesis.
  
  
  METHODS
  We analysed LT formation and performed mechanistic studies in human neutrophils stimulated with pathophysiologically relevant stimuli (LPS and formyl peptide), as well as in cell-free assays (neutrophil homogenates or recombinant human 5-LO) and in human whole blood. The in vivo effectiveness of tryptanthrin was evaluated in the rat model of carrageenan-induced pleurisy.
  
  
  RESULTS
  Tryptanthrin potently reduced LT-formation in human neutrophils (IC(50) = 0.6µM). However, tryptanthrin is not a redox-active compound and did not directly interfere with 5-LO activity in cell-free assays. Similarly, tryptanthrin did not inhibit the release of arachidonic acid, the activation of MAPKs, or the increase in [Ca(2+) ](i) , but it modified the subcellular localization of 5-LO. Moreover, tryptanthrin potently suppressed LT formation in human whole blood (IC(50) = 10µM) and reduced LTB(4) levels in the rat pleurisy model after a single oral dose of 10mg·kg(-1) .
  
  
  CONCLUSIONS
  Our data reveal that tryptanthrin is a potent natural inhibitor of cellular LT biosynthesis with proven efficacy in whole blood and is effective in vivo after oral administration. Its unique pharmacological profile supports further analysis to exploit its pharmacological potential.
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University Jena, Jena, Germany. carlo.pergola@uni-jena.de
authors.forename: C
authors.initials: C
authors.lastname: Pergola
authors.forename: B
authors.initials: B
authors.lastname: Jazzar
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: H
authors.initials: H
authors.lastname: Northoff
authors.forename: M
authors.initials: M
authors.lastname: Hamburger
authors.forename: L
authors.initials: L
authors.lastname: Sautebin
authors.forename: O
authors.initials: O
authors.lastname: Werz
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002351:Carrageenan; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011799:Quinazolines; D017382:Reactive Oxygen Species; C046243:tryptanthrine; D002351:Carrageenan; D001094:Arachidonate 5-Lipoxygenase; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium