The isoprostanes--25 years later

Abstract

Isoprostanes (IsoPs) are prostaglandin-like molecules generated independent of the cyclooxygenase (COX) by the free radical-induced peroxidation of arachidonic acid. The first isoprostane species discovered were isomeric to prostaglandin F2α and were thus termed F2-IsoPs. Since the initial discovery of the F2-IsoPs, IsoPs with differing ring structures have been identified as well as IsoPs from different polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexanenoic acid. The discovery of these molecules in vivo in humans has been a major contribution to the field of lipid oxidation and free radical research over the course of the past 25 years. These molecules have been determined to be both biomarkers and mediators of oxidative stress in numerous disease settings. This review focuses on recent developments in the field with an emphasis on clinical research. Special focus is given to the use of IsoPs as biomarkers in obesity, ischemia-reperfusion injury, the central nervous system, cancer, and genetic disorders. Additionally, attention is paid to diet and lifestyle factors that can affect endogenous levels of IsoPs. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."

Keywords: Biomarker; Isoprostane; Lipid peroxidation; Mass spectrometry; Oxidative stress.

Fig. 1

Mechanism of formation of F₂-isoprostanes from the free radical-cataylzed peroxidation of arachidonic acid. Two primary nomenclature systems have been developed to classify isoprostanes [8,9]. In the nomenclature system used throughout this manuscript, IsoP is used as the abbreviation for isoprostane and the four regioisomer classes are named according to the carbon number on which the side chain hydroxyl group is attached, with the carboxyl carbon being 1 [8]. This nomenclature system has been approved by the Eicosanoid Nomenclature Committee, which is sanctioned by JCBN of IUPAC. The alternative nomenclature system uses the abbreviation iP for isoprostane and the regioisomers are denoted as III–VI based upon the number of carbons between the omega carbon and the first double bond [9].

Fig. 2

Arachidonic acid can be oxidized to many different classes of isoprostanes. F₂-isoprostanes are most commonly used as biomarkers of oxidative stress in human disease but E₂/D₂-isoprostanes have also been used as biomarkers of oxidative stress under certain conditions. Isothromboxanes as well as A₂/J₂-isoprostanes and deoxy-J₂-isoprostanes are also formed.

Fig. 3

Under settings of increased oxygen tension isofurans are formed preferentially to isoprostanes from a common radical intermediate.

Fig. 4

Urinary metabolites of F₂-isoprostanes.