The isoprostanes - unique products of arachidonate peroxidation: their role as mediators of oxidant stress.
The isoprostanes (IsoPs) are a series of novel prostaglandin-like compounds formed in vivo in humans from the free radical-catalyzed peroxidation of arachidonate independent of the cyclooxygenase. While quantification of these compounds is a highly accurate measure of oxidant stress in vivo in humans, IsoPs also possess potent biological activity and likely mediate certain aspects of oxidative injury. The purpose of this review is to summarize selected aspects of our knowledge regarding the bioactivity of the IsoPs. I will first briefly highlight mechanisms involved in IsoP formation. Subsequently, I will discuss the biological activities of certain IsoPs that are formed in abundance in vivo and focus on two compounds, 15-F(2t)-IsoP and 15-E(2t)-IsoP, that have been studied in the greatest detail. This review will then examine, at a molecular level, mechanisms by which IsoPs exert their bioactivity. It has been shown that they are ligands for various eicosanoid receptors, in particular, the thromboxane receptor. In addition, I will discuss the controversial evidence that a unique IsoP receptor(s) exists. Finally, I will offer avenues for future research related to the development of pharmacological approaches to modulate IsoP formation and action in vivo and thus decrease the pathophysiological sequelae of oxidative injury.
Department of Medicine, Vanderbilt University, Nashville, TN 37232-6602, USA. jason.morrow@vanderbilt.edu
Jason D
JD
Morrow
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D028421:Isoprostanes / Q000096:biosynthesis / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D015227:Lipid Peroxidation; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D018384:Oxidative Stress; D011652:Pulmonary Circulation / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000187:drug effects; D058307:Receptors, Prostaglandin E, EP2 Subtype; D017482:Receptors, Thromboxane / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016085:Bronchoconstrictor Agents; D028421:Isoprostanes; C545644:PTGER2 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D016718:Arachidonic Acid; D015237:Dinoprost; D015232:Dinoprostone; C011987:8-isoprostaglandin E2