title: Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4production.
abstract: Propofol is an intravenous anesthetic that produces its anesthetic effect, largelyviathe GABAAreceptor in the CNS, and also reduces theN-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil respiratory burst. Because fMLP-stimulated neutrophils produce leukotriene (LT)B4, we examined the effect of propofol on LTB4productionin vivoandin vitroCecal ligation and puncture surgery was performed in mice, with or without exposure to propofol. Propofol attenuated the production of 5-lipoxygenase (5-LOX)-related arachidonic acid (AA) derivatives in the peritoneal fluid. Also, in thein vitroexperiments on fMLP-stimulated neutrophils and 5-LOX-transfected human embryonic kidney cells, propofol attenuated the production of 5-LOX-related AA derivatives. Based on these results, we hypothesized that propofol would directly affect 5-LOX function. Usingmeta-azi-propofol (AziPm), we photolabeled stable 5-LOX protein, which had been used to solve the X-ray crystallographic structure of 5-LOX, and examined the binding site(s) of propofol on 5-LOX. Two propofol binding pockets were identified near the active site of 5-LOX. Alanine scanning mutagenesis was performed for the residues of 5-LOX in the vicinity of propofol, and we evaluated the functional role of these pockets in LTB4production. We demonstrated that these pockets were functionally important for 5-LOX activity. These two pockets can be used to explore a novel 5-LOX inhibitor in the future.-Okuno, T., Koutsogiannaki, S., Ohba, M., Chamberlain, M., Bu, W., Lin, F.-Y., Eckenhoff, R. G., Yokomizo T., Yuki, K. Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4production.
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Division of Cardiac Anesthesia, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston Massachusetts, USA.|Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Koutsogiannaki
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Ohba
authors.affiliation: Division of Cardiac Anesthesia, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston Massachusetts, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Chamberlain
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; and.
authors.forename: Weiming
authors.initials: W
authors.lastname: Bu
authors.affiliation: Immune Disease Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Fu-Yan
authors.initials: FY
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; and.
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Division of Cardiac Anesthesia, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston Massachusetts, USA; koichi.yuki@childrens.harvard.edu.|Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yuki
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D018686:Anesthetics, Intravenous; D001095:Arachidonic Acids; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D015742:Propofol
keywords: anesthesia; inhibitor; lipid mediator