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5-Lipoxygenase-mediated Endogenous DNA Damage
Recent JBC article titled "5-Lipoxygenase-mediated endogenous DNA damage" in the Spotlight section of ACS Chemical Research in Toxicology’s July issue:
SPOTLIGHT: Inflammatory DNA Damage
5-Lipoxygenase (5-LO), acting coordinately with the 5-LO activating protein (FLAP), oxygenates arachidonic acid (AA) to form 5(S)-hydroperoxyeicosatetraenoic acid (5(S)-HpETE). 5(S)-HpETE can be reduced to the corresponding alcohol, or enzymatically converted to the biologically active leukotrienes. 5(S)-HpETE is also subject to homolytic decomposition to form bifunctional electrophiles that can react with cellular constituents such as DNA and proteins.
5-LO and FLAP are expressed predominantly in inflammatory cells, so 5-LO-derived reactive electrophiles could damage DNA during the inflammatory response. Jian, et al. [(2009) J. Biol. Chem. published online April 23, DOI:10.1074/jbc.M109/011841] have tested this hypothesis in the human lymphoblastic CESS cell line, which expresses 5-LO, FLAP, and cyclooxygenase 1 (COX-1), but no other enzymes of AA metabolism.
Following treatment of CESS cells with ionophore A23187 to induce AA metabolism, chiral LC-electron capture APCI/MRM/MS analysis of culture medium confirmed the biosynthesis of products of the 5-LO and COX-1 pathways. LC-APCI/MRM/MS analysis also revealed an increase in the level of heptanone-etheno-2’-deoxyguanosine (H?dGuo), a DNA adduct formed from a 5(S)-HpETE decomposition product. Treatment of the cells with the FLAP inhibitor MK886 prevented the A23187-mediated increase in H?dGuo, while treatment with the COX-1 inhibitor aspirin had no effect. Vitamin C, which promotes homolytic decomposition of 5(S)-HpETE facilitated A23187-mediated H?dGuo formation. The data suggest a role for 5-LO in promoting DNA damage during the inflammatory response.