Products of the isoprostane pathway: unique bioactive compounds and markers of lipid peroxidation

Abstract.

We previously reported the discovery of prostaglandin F₂-like compounds (F₂-isoprostanes) formed by nonenzymatic free-radical-induced peroxidation of arachidonic acid. Quantification of F₂-isoprostanes has proven to be a major advance in assessing oxidative stress status in vivo. Central in the pathway of formation of isoprostanes are prostaglandin H₂-like endoperoxides, which also undergo rearrangement in vivo to form E-ring, D-ring, and thromboxane-ring compounds. E₂- and D₂-isoprostanes also undergo dehydration in vivo to form reactive cyclopentenone A₂- and J₂-isoprostanes, which are susceptible to Michael addition reactions with thiols. Recently, we described the formation of highly reactive γ-ketoaldehydes (now termed isoketals) as products of isoprostane endoperoxide rearrangement which readily adduct to lysine residues on proteins and induce cross-links at rates that far exceed other aldehyde products of lipid peroxidation. Isoprostane-like compounds (neuroprostanes) and isoketal-like compounds (neuroketals) are formed from oxidation of docosahexaenoic acid, which is enriched in the brain, and measurement of neuroprostanes may provide a unique marker of oxidative neuronal injury.