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

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 F-2 alpha (8-iso-PGF(2 alpha)), which has been measured in over a thousand human and animal studies. 8-iso-PGF(2 alpha) generation has been exclusively attributed to nonenzymatic chemical lipid peroxidation (CLP). However, 8-iso-PGF(2 alpha) can also be produced enzymatically by prostaglandin-endoperoxide synthases (PGHS) in vivo. When failing to account for PGHS-dependent generation, 8-iso-PGF(2 alpha) cannot be interpreted as a selective biomarker of oxidative stress. We investigated the formation of 8-iso-PGF(2 alpha) in rats exposed to carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) using the 8-iso-PGF(2 alpha)/PGF(2 alpha) ratio to quantitatively determine the source(s) of 8-iso-PGF(2 alpha). Upon exposure to a 120 mg/kg dose of CCl4, the contribution of CLP accounted for only 55.6 +/- 19.4% of measured 8-iso-PGF(2 alpha), whereas in the 1200 mg/kg dose, CLP was the predominant source of 8-iso-PGF(2 alpha) (86.6 +/- 8.0% of total). In contrast to CCl4, exposure to 0.5 mg/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-PGF(2 alpha) 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-PGF(2 alpha)/PGF(2 alpha) ratio accurately determines the source of 8-iso-PGF(2 alpha) and provides an absolute measure of oxidative stress in vivo. (C) 2016 Published by Elsevier Inc.