title: Reinterpreting the best biomarker of oxidative stress: The 8-iso-prostaglandin F2α/prostaglandin F2α ratio shows complex origins of lipid peroxidation biomarkers in animal models.
abstract: Oxidative stress is elevated in numerous environmental exposures and diseases. Millions of dollars have been spent to try to ameliorate this damaging process using anti-oxidant therapies. Currently, the best accepted biomarker of oxidative stress is the lipid oxidation product 8-iso-prostaglandin F2α (8-iso-PGF2α), which has been measured in over a thousand human and animal studies. 8-iso-PGF2α generation has been exclusively attributed to nonenzymatic chemical lipid peroxidation (CLP). However, 8-iso-PGF2α can also be produced enzymatically by prostaglandin-endoperoxide synthases (PGHS) in vivo. When failing to account for PGHS-dependent generation, 8-iso-PGF2α cannot be interpreted as a selective biomarker of oxidative stress. We investigated the formation of 8-iso-PGF2α in rats exposed to carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) using the 8-iso-PGF2α/PGF2α ratio to quantitatively determine the source(s) of 8-iso-PGF2α. Upon exposure to a 120mg/kg dose of CCl4, the contribution of CLP accounted for only 55.6±19.4% of measured 8-iso-PGF2α, whereas in the 1200mg/kg dose, CLP was the predominant source of 8-iso-PGF2α (86.6±8.0% of total). In contrast to CCl4, exposure to 0.5mg/kg LPS was characterized by a significant increase in both the contribution of PGHS (59.5±7.0) and CLP (40.5±14.0%). In conclusion, significant generation of 8-iso-PGF2α occurs through enzymatic as well as chemical lipid peroxidation. The distribution of the contribution is dependent on the exposure agent as well as the dose. The 8-iso-PGF2α/PGF2α ratio accurately determines the source of 8-iso-PGF2α and provides an absolute measure of oxidative stress in vivo.
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 27709 NC, USA. Electronic address: thomas.vanterve@nih.gov.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Van't Erve
authors.affiliation: Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 27709 NC, USA.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Department of Statistics, West Virginia University, Morgantown, WV 26505, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Jelsema
authors.affiliation: Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 27709 NC, USA.
authors.forename: Leesa J
authors.initials: LJ
authors.lastname: Deterding
authors.affiliation: Emeritus, National Institute of Environmental Health Sciences, Research Triangle Park, 27709 NC, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 27709 NC, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mason
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 27709 NC, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Kadiiska
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000633:toxicity; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018384:Oxidative Stress / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D008070:Lipopolysaccharides; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D002251:Carbon Tetrachloride; D011451:Prostaglandin-Endoperoxide Synthases
keywords: 8-iso-PGF(2α)/PGF(2α) ratio; Biomarkers; F(2)-isoprostanes; Inflammation; Lipid peroxidation; Oxidative stress