Review ArticleLipid peroxidation: Physiological levels and dual biological effects
Introduction
Lipid peroxidation (LPO) [1] was first studied in relation to the deterioration of foods in 1930s, when the study on the chemistry of free radical reactions made remarkable advancements [2], [3]. With increasing evidence showing the involvement of free radicals in biology [4], [5], [6], [7], LPO has received renewed attention from wider viewpoints in the fields of chemistry, biochemistry, biology, nutrition, and medicine. Later studies revealed that, like proteins, carbohydrates, and nucleic acids, lipids are targets of various reactive oxygen and nitrogen species, ROS/RNS, and oxidized to give a diverse array of products. The mechanisms, dynamics, and products of LPO in vitro have been studied extensively and are now fairly well understood and documented [8], [9], [10], but the physiological levels and biological effects of LPO and its products have not been well elucidated yet. It has been shown that LPO induces disturbance of fine structures, alteration of integrity, fluidity, and permeability, and functional loss of biomembranes, modifies low density lipoprotein (LDL) to proatherogenic and proinflammatory forms, and generates potentially toxic products [11]. LPO products have been shown to be mutagenic and carcinogenic [12]. As described later, the reactive carbonyl compounds, the secondary products of LPO, modify biologically essential molecules such as proteins and DNA bases [13], [14], [15]. Thus LPO in vivo has been implicated as the underlying mechanisms in numerous disorders and diseases such as cardiovascular diseases, cancer, neurological disorders, and aging. Consistent with this notion, numerous studies show increased levels of LPO products in the biological fluids and tissues from the patients, although the question whether LPO is a cause or consequence of these events is still not clear and remains to be elucidated in the future studies.
At the same time, it became evident recently that LPO products as well as ROS/RNS exert various biological functions in vivo such as regulators of gene expression, signaling messengers, activators of receptors and nuclear transcription factors, and inducers of adaptive responses [16], [17], [18], [19], [20]. Recent studies provided evidence that many LPO products exert opposite dual effects depending on the conditions, such as cytotoxic and cytoprotective effects, pro- and antiatherogenic effects, pro- and antiapoptotic effects, and pro- and anti-inflammatory effects [20], [21]. However, the physiological significance of such effects by LPO products is not clear yet.
Pryor et al. pointed out that one of the greatest needs in the field of free radical biology is the development of reliable measures of oxidative stress status (OSS), biomarkers, in humans [22]. If OSS is elevated in particular disease states, then we could ask if oxidative stress is a cause or an effect of disease state and also whether antioxidants can lessen and/or ameliorate the disease state. The reliable measures should be effective also for monitoring healthy states and assessing the beneficial effects of antioxidants contained in foods, fruits, beverages, and supplements. Numerous biomarkers for OSS have been proposed and measured, including LPO products and oxidatively modified proteins and DNA [23]. In this article, the physiological levels of LPO products and their potential biological effects will be reviewed.
Section snippets
Mechanisms, dynamics, and products of LPO
First, the mechanisms, dynamics, and products of LPO will be briefly reviewed. The understanding of these basic issues is essential for sound interpretation of the biological data. It has been well documented that the LPO proceeds by three distinct mechanisms, that is, (1) free radical-mediated oxidation, (2) free radical-independent, nonenzymatic oxidation, and (3) enzymatic oxidation [24]. Specific products are formed from the respective mechanism and specific antioxidants are required to
Physiological levels of LPO products in human
As shown above, the LPO produces a vast variety of products by different mechanisms and it is quite difficult to identify and quantify all of them. Furthermore, these products are readily metabolized and excreted by efficient defense mechanisms in vivo and the levels of LPO products measured in biological fluids and tissues reflect the balance among formation, metabolism, clearance, and excretion. Further, the diet contains various LPO products and the measurement of LPO levels in biological
Induction of adaptive response by LPO products
It has been shown that LPO products exert various biological effects either directly by reacting with proteins, enzymes, and nucleic acids or indirectly through receptor-mediated pathways [15], [16], [17], [18], [19], [20], [21], [181], [182], [183]. LPO alters chemical characteristics and physical organization of cellular membranes to induce functional loss and modifies lipoproteins to proatherogenic and proinflammatory forms. LPO products are assumed to be pathogenic and contribute to the
Concluding remarks
There is no doubt that LPO proceeds in vivo and that LPO and its products exert deleterious effects under certain conditions. Numerous studies show the association between the levels of LPO product increases and the progress of oxidative stress-related diseases [23], [187], [231], [232], [233], [234], [235], [236], although it is not clear yet whether LPO is important as a cause or it is a consequence. At the same time, LPO products may play a role as a cellular regulator and signaling
Acknowledgments
I thank my colleagues whose names appear as coauthors of the cited papers from our group for their invaluable contribution. I also appreciate many suggestive comments from the reviewers, which were helpful for strengthening this article.
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