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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: 5-Lipoxygenase-mediated endogenous DNA damage.

Authors: Jian, Wenying; Lee, Seon Hwa; Williams, Michelle V; Blair, Ian A

Published In J Biol Chem, (2009 Jun 19)

Abstract: Lipoxygenases (LOs) convert polyunsaturated fatty acids into lipid hydroperoxides. Homolytic decomposition of lipid hydroperoxides gives rise to endogenous genotoxins such as 4-oxo-2(E)-nonenal, which cause the formation of mutagenic DNA adducts. Chiral lipidomics analysis was employed to show that a 5-LO-derived lipid hydroperoxide was responsible for endogenous DNA-adduct formation. The study employed human lymphoblastoid CESS cells, which expressed both 5-LO and the required 5-LO-activating protein (FLAP). The major lipid peroxidation product was 5(S)-hydroperoxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid, which was analyzed as its reduction product, 5(S)-hydroxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid (5(S)-HETE)). Concentrations of 5(S)-HETE increased from 0.07 +/- 0.01 to 45.50 +/- 4.05 pmol/10(7) cells upon stimulation of the CESS cells with calcium ionophore A23187. There was a concomitant increase in the 4-oxo-2(E)-nonenal-derived DNA-adduct, heptanone-etheno-2'-deoxyguanosine (HepsilondGuo) from 2.41 +/- 0.35 to 6.31 +/- 0.73 adducts/10(7) normal bases. Biosynthesis of prostaglandins, 11(R)-hydroxy-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid, and 15(R,S)-hydroxy-5,8,11,13-(Z,Z,Z,E)-eicosatetraenoic acid revealed that there was cyclooxygenase (COX) activity in the CESS cells. Western blot analysis revealed that COX-1 was expressed by the cells, but there was no COX-2 or 15-LO-1. FLAP inhibitor reduced HepsilondGuo-adducts and 5(S)-HETE to basal levels. In contrast, aspirin, which had no effect on 5(S)-HETE, blocked the formation of prostaglandins, 15-HETE, and 11-HETE but did not inhibit HepsilondGuo-adduct formation. These data showed that 5-LO was the enzyme responsible for the generation of the HepsilondGuo DNA-adduct in CESS cells.

PubMed ID: 19390118 Exiting the NIEHS site

MeSH Terms: 5-Lipoxygenase-Activating Proteins; Arachidonate 5-Lipoxygenase/metabolism*; Aspirin/pharmacology; Calcimycin/pharmacology; Carrier Proteins/antagonists & inhibitors; Carrier Proteins/metabolism; Cell Line; Cyclooxygenase 1/metabolism; DNA Adducts/biosynthesis; DNA Damage/physiology*; Humans; Hydroxyeicosatetraenoic Acids/biosynthesis; Ionophores/pharmacology; Leukotriene B4/biosynthesis; Lipid Peroxidation; Lymphocytes/drug effects; Lymphocytes/metabolism; Membrane Proteins/antagonists & inhibitors; Membrane Proteins/metabolism; Models, Biological; Prostaglandins/biosynthesis

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