title: Activation of 5-lipoxygenase and NF-kappa B in the action of acenaphthenequinone by modulation of oxidative stress.
abstract: Quinoid polycyclic aromatic hydrocarbons are potent redox-active compounds that undergo enzymatic and nonenzymatic redox cycling with their semiquinone radical. We previously reported that acenaphthenequinone (AcQ) can damage human lung epithelial A549 cells through the formation of reactive species (RS). However, the biochemical mechanisms by which RS-generating enzymes cause oxidative burst during AcQ exposure remain elusive. Here we examined the biochemical mechanism of AcQ-induced RS generation by using selective metabolic inhibitors in A549 cells. We found that AA861, a 5-lipoxygenase (5-LO)-specific inhibitor significantly decreases RS generation. This inhibition of RS seems to be 5-LO specific because other inhibitors did not suppress AcQ-induced RS generation by nicotinamide adenine nucleotide phosphate (reduced) oxidase and/or xanthine oxidase. In addition, the inhibition of 5-LO by AA861 markedly reduced AcQ-induced nuclear factor kappa B (NF-kappa B) activation. We further found the activation of 5-LO pathway by exposing cells to AcQ mediates the secretion of inflammatory leukotriene B4, which can be significantly suppressed by a potent RS scavenger, N-acetylcysteine. Thus, based on our findings, we propose that AcQ-induced damage is likely due to increased RS generation and NF-kappa B activity through 5-LO activation.
authors.affiliation: Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. chungsw@p.kanazawa-u.ac.jp
authors.forename: Sang Woon
authors.initials: SW
authors.lastname: Chung
authors.forename: Akira
authors.initials: A
authors.lastname: Toriba
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kameda
authors.forename: Ning
authors.initials: N
authors.lastname: Tang
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Kizu
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Hayakawa
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D007202:Indicators and Reagents; D007249:Inflammation / Q000503:physiopathology; D007975:Leukotriene B4 / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000073:Acenaphthenes; D000975:Antioxidants; D016227:Benzoquinones; D007202:Indicators and Reagents; D016328:NF-kappa B; D007975:Leukotriene B4; C023722:acenaphthenequinone; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001093:Arachidonate 15-Lipoxygenase; D008156:Luciferases; D000111:Acetylcysteine