Classifying oxidative stress by F2-Isoprostane levels in human disease: The re-imagining of a biomarker☆

Oxidative stress as classified by F2-Isoprostanes (F2-IsoPs) in Human Disease: Grab the Low-Hanging Fruit – The utility of F2-IsoPs as a biomarker of oxidative injury in human disease is complex. Careful consideration of the formation, metabolism, and measurement of this biomarker is imperative in the design of clinical trials. Conditions with significantly elevated levels of F2-IsoPs are ideal candidates for targeting new generation antioxidant therapies in clinically relevant situations. Oxidative damage to lipids, particularly during the storage of oils, dates to antiquity. The first evidence of lipid peroxidation was described by Senebier in 1791 when he described that olive oil kept in air lost its fluidity and obtained a bad smell while another sample not exposed air remain unchanged [1]. Yet, it was nearly 200 years later that specific products generated during the oxidation of polyunsaturated fatty acids (PUFAs) were first identified and the importance of PUFA oxidation in biological systems was illuminated. Tappel first introduced the free radical theory of aging in 1968 when he proposed that antioxidants would slow the aging process [2]. In 1985, Sies and Cadenas first introduced the term ‘oxidative stress’ and defined it as ‘a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage [3,4].’ Sies and Jones have since updated the definition to ‘an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage [5].’ A primary target of molecular damage resulting from oxidative stress is PUFA. One crucial stumbling block to the study of oxidative stress in human physiology and pathophysiology has been the availability of effective biomarkers to not only assess oxidative injury but to also identify the effectiveness of potential therapies to decrease damage. Many of the common early markers of lipid peroxidation, including TBARS, malondialdehyde (MDA), and lipid hydroperoxides (LOOHs), are now considered ineffective as biomarkers due to their reactivity, metabolism, or unreliable methods of quantification [6]. Following the accidental discovery of the F2-isoprostanes (F2-IsoPs) by Morrow and Roberts in 1991, the field rapidly embraced the measurement of these compounds, as it seemed that these molecules fit the magic bullet description of the perfect biomarker [7–10]. First and foremost, the F2IsoPs are relatively chemical stable, especially compared to TBARS, MDA, and LOOHs. Importantly, they are ubiquitous in human plasma and urine and, consequently, normal levels could be defined. Further, early studies showed increases in these molecules in diseases and lifestyle factors classically associated with oxidative stress (ie. atherosclerosis, hyperlipidemia, smoking, etc.) Yet, despite more than 4000 published works on IsoPs in the past 25 years, F2-IsoPs are still not considered a clinically relevant biomarker.