Identification of novel oxidized levuglandin D ₂in marine red alga and mouse tissue

In animals, the product of cyclooxygenase reacting with arachidonic acid, prostaglandin(PG)H ₂, can undergo spontaneous rearrangement and nonenzymatic ring cleavage to form levuglandin(LG)E ₂ and LGD ₂. These LGs and their isomers are highly reactive γ-ketoaldehydes that form covalent adducts with proteins, DNA, and phosphatidylethanolamine in cells. Here, we isolated a novel oxidized LGD ₂ (ox-LGD ₂) from the red alga Gracilaria edulis and determined its planar structure. Additionally, ox-LGD ₂ was identified in some tissues of mice and in the lysate of phorbol-12-myristate-13-acetate (PMA)-treated THP-1 cells incubated with arachidonic acid using LC-MS/MS. These results suggest that ox-LGD ₂ is a common oxidized metabolite of LGD ₂. In the planar structure of ox-LGD ₂, H8 and H12 of LGD ₂ were dehydrogenated and the C9 aldehyde was oxidized to a carboxylic acid, which formed a lactone ring with the hydrated ketone at C11. These structural differences imply that ox-LGD ₂ is less reactive with amines than LGs. Therefore, ox-LGD ₂ might be considered a detoxification metabolite of LGD ₂.