title: Atrovirinone inhibits pro-inflammatory mediator release from murine macrophages and human whole blood.
abstract: Many plant-derived natural compounds have been reported previously to inhibit the production of important pro-inflammatory mediators such as nitric oxide, prostaglandin E2, TNF-alpha and reactive oxygen species by suppressing inducible enzyme expression via inhibition of the mitogen-activated protein kinase pathway and nuclear translocation of critical transcription factors. This study evaluates the effects of atrovirinone [2-(1-methoxycarbonyl-4,6-dihydroxyphenoxy)-3-methoxy-5,6-di-(3-methyl-2-butenyl)-1,4-benzoquinone)], a benzoquinone that we have previously isolated from Garcinia atroviridis, on two cellular systems that are repeatedly used in the analysis of anti-inflammatory bioactive compounds, namely, RAW 264.7 macrophage cells and whole blood. Atrovirinone inhibited the production of both nitric oxide and prostaglandin E2 from LPS-induced and IFN-gamma-induced RAW 264.7 cells and whole blood, with inhibitory concentration (IC)50 values of 4.62 +/- 0.65 and 9.33 +/- 1.47 micromol/L, respectively. Analysis of thromboxane B2 (TXB2) secretion from whole blood stimulated by either the cyclooxygenase (COX)-1 or the COX-2 pathway showed that atrovirinone inhibits the generation of TXB2 by both pathways, with IC50 values of 7.41 +/- 0.92 and 2.10 +/- 0.48 micromol/L, respectively. Analysis of IC50 ratios showed that atrovirinone was more COX-2 selective in its inhibition of TXB2, with a ratio of 0.32. Atrovirinone also inhibited the generation of intracellular reactive oxygen species and the secretion of TNF-alpha from RAW 264.7 cells in a dose-responsive manner, with IC50 values of 5.99 +/- 0.62 and 11.56 +/- 0.04 micromol/L, respectively. Lipoxygenase activity was also moderately inhibited by atrovirinone. Our results suggest that atrovirinone acts on important pro-inflammatory mediators possibly by the inhibition of the nuclear factor-kappaB pathway and also by the inhibition of the COX/lipoxygenase enzyme activity.
authors.affiliation: Institute of Bioscience, University of Putra Malaysia, Serdang, Selangor, Malaysia.
authors.forename: A
authors.initials: A
authors.lastname: Syahida
authors.forename: Daud A
authors.initials: DA
authors.lastname: Israf
authors.forename: D
authors.initials: D
authors.lastname: Permana
authors.forename: N H
authors.initials: NH
authors.lastname: Lajis
authors.forename: S
authors.initials: S
authors.lastname: Khozirah
authors.forename: A W
authors.initials: AW
authors.lastname: Afiza
authors.forename: T A
authors.initials: TA
authors.lastname: Khaizurin
authors.forename: M N
authors.initials: MN
authors.lastname: Somchit
authors.forename: M R
authors.initials: MR
authors.lastname: Sulaiman
authors.forename: A A
authors.initials: AA
authors.lastname: Nasaruddin
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008084:Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C435805:atrovirinone; D009569:Nitric Oxide; D007371:Interferon-gamma; D008084:Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone