Molecular and biological mechanisms of antioxidant action

There is increasing evidence that oxidative stress, defined as an imbalance between oxidants and antioxidants in favor of the former, leads to many biochemical changes and is an important contributing factor in several human chronic diseases, such as atherosclerosis and cardiovascular diseases, mutagenesis and cancer, several neurodegenerative disorders, and likely the aging process per se. For example, we know that lipid peroxidation products and oxidized forms of low density lipoproteins accumulate in atherosclerotic lesions, and that numerous modified DNA bases are formed under conditions of oxidative stress and are highly mutagenic, such as 8-oxo-guanine. For many of these oxidatively modified biomolecules, there are repair enzymes, including numerous peroxidases that reduce lipid hydroperoxides to their corresponding alcohols and glycosylases that remove specific DNA lesions. In addition to repairing oxidatively damaged biomolecules, another layer of defense against oxidative stress and resultant damage is to prevent formation of reactive oxygen and nitrogen species or to scavenge these species before they can cause oxidative damage to biomolecules. Among these defenses are antioxidant enzymes, which are mostly intracellular and include several forms of superoxide dismutases and catalase. The antioxidant enzymes are complemented by small-molecule antioxidants, some of which are derived exclusively from the diet and are vitamins. These small-molecule antioxidants are present extra-and intracellularly, and include ascorbic acid (vitamin C), glutathione (GSH), and tocopherols (primarily α-tocopherol; vitamin E). Intracellular concentrations of these compounds can be substantial, i.e., in the millimolar range both for ascorbate and GSH. α-Tocopherol is by far the most abundant lipid-soluble antioxidant in humans, present in cellular and subcellular membranes and lipoproteins. The mechanisms by which these antioxidants act at the molecular and cellular level include roles in gene expression and regulation, apoptosis, and signal transduction. Thus, antioxidants are involved in fundamental metabolic and homeostatic processes. However, there are still many gaps in our knowledge of the basic mechanisms of oxidative damage and antioxidant defenses. Filling these gaps would allow us to more specifically target treatments and derive optimal benefits from antioxidants for health promotion and disease prevention. Therefore, in August of 1998, 37 national and international experts in free radical and antioxidant (bio)chemistry and cell biology met in Copper Mountain, Colo., to present their latest findings to ∼150 participants at a FASEB summer research conference entitled “Molecular and Biological Mechanisms of Antioxidant Action.” This conference presented a contemporary view of the mechanisms of oxidative damage to lipids, proteins, and DNA and the molecular, biochemical, and physiological action of antioxidants and their role in cell biology, with a focus on small molecule antioxidants. The sessions covered the following topics: molecular mechanisms of oxidative damage; vitamin C, vitamin E, and GSH: metabolism, antioxidant (inter)actions, and pro-oxidant vs. antioxidant effects; novel aspects of vitamin E metabolism and action; nitric oxide and radical-mediated toxicity; and (anti)oxidant regulation of gene expression: transcription factors, nuclear response elements, and apoptotic cell death. This and the July issue of The FASEB Journal contain several articles selected from each of these sessions and written by the speakers. The purpose of these reviews is to provide in-depth coverage of each topic, with emphasis on the most groundbreaking developments. Thus, in this issue, Keaney et al. (1) discuss the role of vitamin E as a protein kinase C inhibitor in improving the biological activity of endothelium-derived nitric oxide and limiting platelet aggregation and monocyte adhesion; Stocker's group (2) explains the novel concept of tocopherol-mediated lipid peroxidation in lipoproteins and the conditions under which α-tocopherol acts as an antioxidant or a pro-oxidant; May (3) discusses the mechanisms of cellular ascorbate recycling and a transmembrane, ascorbate-dependent oxidoreductase activity; and Carr and I (4) review the mechanisms by which vitamin C may act as a pro-oxidant and the evidence in support of or against a role of vitamin C in causing oxidative damage to biomolecules under physiological conditions. In the July issue of the journal, articles will address the current concepts and controversies of hepatic GSH synthesis; provide new insights into the metabolism and function of vitamin E; focus on the mechanisms of oxidative damage to biomolecules, including lipid peroxidation and isolevuglandin formation, protein oxidation and its role in atherogenic low density lipoprotein modification, and the intriguing link between nitric oxide and the cyclooxygenases; and, finally, discuss the role of oxidants and antioxidants in signaling mechanisms in apoptosis and activation of the transcription factor nuclear factor κB. I thank FASEB for supporting the conference and the journal for the invitation to edit this exciting series. I am grateful to my co-chair, Maret Traber, from the Linus Pauling Institute, the vice chairs Lester Packer and Steven Tannenbaum, to all who participated as speakers at the conference, and the authors and reviewers of the articles. Without the excellent contributions of these scientists, the conference and the proceedings would not have been possible.