We previously discovered a series of novel prostaglandin (PG) F/2-like compounds, termed F/2- isoprostanes, produced in vivo in humans by a non- cyclooxygenase free radical catalyzed mechanism. More recently we have discovered that isoprostanes with prostane D/E-type rings are also produced by this mechanism in vivo. D/E-type isoprostanes are formed by rearrangement of PGG/2-like endoperoxides which are intermediates in the formation of isoprostanes. The formation of D/E-isoprostanes increases dramatically in animal models of lipid peroxidation and these compounds are capable of exerting potent biological activity. Studies are thus proposed to further investigate the biochemistry and pharmacology of this class of isoprostanes. D/2/E/2-isoprostanes have been characterized and quantified by mass spectrometry. Studies are proposed to further refine this method. We have obtained evidence that the relative ratio of D/E-type to F-type isoprostanes is influenced by factors such as glutathione which may modulate the reduction of isoprostane endoperoxide intermediates to F/2- isoprostanes and that this reduction may also be catalyzed by an enzyme. Studies will investigate further factors that modulate the formation of D/2/E/2-isoprostanes relative to F/2-isoprostanes both in vitro and in vivo. Little is known about the metabolic fate of D/E-type isoprostanes. We have obtained evidence suggesting that D/2/E/2-isoprostanes are conjugated with glucuronic acid in vivo and studies are proposed to further establish this pathway of metabolism. Studies will also investigate non-conjugated pathways of metabolism of the isoprostanes in in vitro systems and in vivo in the monkey. We have found that the isoprostane, 8-iso-PGE/2, is a potent vasoconstrictor of renal vasculature. Studies thus are proposed to further characterize the biological activity of the D/2/E/2-isoprostanes. Evidence suggests that 8-iso-PGE/2 exerts its vascular effects via interaction with a novel receptor and studies will characterize this receptor further using radioligand binding approaches. These studies should provide insights regarding the value of quantifying D/2/E/2-isoprostanes as a marker of lipid peroxidation in vivo and advance our understanding of the role of these compounds as mediators of oxidant injury.
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