Activation of 5-lipoxygenase and NF-kappa B in the action of acenaphthenequinone by modulation of oxidative stress.
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.
Chung
Sang Woon
SW
Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. chungsw@p.kanazawa-u.ac.jp
Toriba
Akira
A
Chung
Hae Young
HY
Yu
Byung Pal
BP
Kameda
Takayuki
T
Tang
Ning
N
Kizu
Ryoichi
R
Hayakawa
Kazuichi
K
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
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