Levuglandins and isolevuglandins: stealthy toxins of oxidative injury.

Inspired by a reaction discovered through basic research on the chemistry of the bicyclic peroxide nucleus of the prostaglandin endoperoxide PGH2, we postulated that levulinaldehyde derivatives with prostaglandin side chains, levuglandins (LGs), and structurally isomeric analogues, isolevuglandins (iso[n]LGs), would be generated by nonenzymatic rearrangements of prostanoid and isoprostanoid endoperoxides. Two decades of subsequent studies culminated in our discoveries of the LG and isoLG pathways, branches of the cyclooxygenase and isoprostane pathways, respectively. In cells, PGH2 rearranges nonenzymatically to LGs even in the presence of enzymes that use PGH2 as a substrate. IsoLGs, also known as isoketals or neuroketals, are generated in vivo through free radical-induced autoxidation of polyunsaturated phospholipid esters. Hydrolysis occurs after rapid adduction of isoLG phospholipids to proteins. The proclivity of these reactive species to avidly bind covalently with and cross-link proteins and nucleic acids complicated the hunt for LGs and isoLGs in vivo. The extraordinary reactivity of these "stealthy toxins" underlies much, if not all, of the biological consequences of LG and isoLG generation. They interfere with protein function and are among the most potent neurotoxic products of lipid oxidation known. Because they can accumulate over the lifetimes of proteins, iso[n]LG-protein adducts represent a convenient dosimeter of oxidative stress.