Human Biochemistry of the Isoprostane Pathway*

Free radicals derived primarily from molecular oxygen have been implicated in a variety of human disorders including atherosclerosis, cancer, neurodegenerative diseases, and aging (1). Damage to tissue biomolecules, including lipids, proteins, and DNA, by free radicals is postulated to contribute importantly to the pathophysiology of oxidative stress. Lipids are readily attacked by free radicals resulting in the formation of a number of peroxidation products. One class of oxidation products formed in abundance in vitro and in vivo is the isoprostanes (IsoPs),2 which were discovered by our laboratory in 1990. IsoPs are a series of prostaglandin (PG)-like compounds produced by the free radical-catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase (2). Over the past 20 years, we and others have carried out a large number of studies defining the basic chemistry and biochemistry involved in the formation and metabolism of the IsoPs. In addition, we have shown that levels of IsoPs are increased in a number of human diseases, and it is currently recognized that measurement of these molecules is the most accurate analytical method to assess oxidative injury in vivo. Further, a number of IsoPs have been found to possess potent biological activity and thus are likely also mediators of oxidant injury (3). In recent years, additional related compounds, derived from various polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) (4) and docosahexaenoic acid (DHA) (5), have been discovered to be formed as products of the IsoP pathway. It is the purpose herein to summarize our current knowledge regarding the IsoPs including the chemistry and biochemistry of their formation, the utility of measuring these compounds as markers of in vivo oxidant stress, and their pharmacological properties.