Advances in Free Radical Biology & Medicine最新文献

Damage to a tissue following ischemia appears top occur during its reperfusion with oxygenated blood. This damage is apparently oxidative in nature and is generally considered to be the result of excessive superoxide (O₂⁻ and hydrogen peroxide (H₂O₂) production. Since neither O₂⁻ nor H₂O₂ cause oxidative damage in the absence of iron, we proposed that the oxidative processes are caused by the released of iron during reperfusion. The damage caused by the iron is exacerbated by hypoperfusion and the loss of calcium homeostasis. Our hypothesis is supported by the finding of significant levels of low molecular weight, chelatable iron in tissues during reperfusion following ischemia. The tissue damage can be ameliorated by techniques that increase the rate of reperfusion (open chest direct heart massage for the cardiac arrest model) and the administration of an iron chelator plus a calcium antagonist. Animals treated in this manner appear to completely recover from 15 minutes of cardiac arrest.

Free radicals including superoxide have been proposed to mediate a variety of cellular responses including phagocytosis, ischemic tissue injury, aging and cancer. However, it has only been in recent years that procedures have been developed which allows one to study the role free radicals play in cellular injury. One such method that has received considerable attention is spin trapping. This technique consists of using a nitrone or a nitroso compound to “trap” the initial unstable free radical as a “long-lived” nitroxide that can be observed at room temperature using convention ESR spectrometric procedures. This review examines how a number of investigators have employed spin trapping methodologies to study the generation of free radicals as a consequence of biological activation by drugs and other foreign compounds.

An extensive discussion is presented of the mechanisms of action of clinically useful anticancer agents in which free radical intermediates have been implicated in their cytotoxic action and/or metabolism. In addition the several factors contributing to drug metabolism and activation and interaction with macromolecular cell targets are discussed as they relate to free radical pathways. Consideration is also given to the action and levels in different tissues of cell protective enzymes against oxidative lesions and the clinicnal implication to anticancer drug action and toxicity.

Lipoxygenase (linoleate: oxygen oxidoreductase EC 1.13.11.12) participates in the oxidation of polyunsaturated fatty acids to specific hydroperoxides. The mechanism is presumed to be a free radical reaction. Secondary reactions, particularly those involving plant pigments, are discussed and possible pathways for bleaching are presented.

The energetics of reactions involving oxyradicals are reviewed. Thermodynamic data of radical species containing O and H are presented first, followed by those of metallocomplexes and metalloproteins, halogen containing species and organic radicals. Our approach is to calculate Gibb energy changes with the help of reduction potentials. If a particular potential is unknown, we estimate it by way of a thermodynamic cycle. The number of assumptions and estimates increases with the order of the topics covered. Thus, our calculations regarding reactions involving H and O containing species are quite rigorous, while conclusions related to organic radicals are more tentative. In particular reactions of hydrogen peroxide, metal ions in lower oxidation states, hydroquinones, hypohalide ions and ascorbic acid leading to short-lived species such as superoxide radical, hydroxyl radical and singlet oxygen are discussed. Appendices contain conventions regarding electrode potentials and solubility data of oxygen in water.

The human neutrophil generates a non-mitochondrial respiratory burst by the activation of a NADPH-oxidase, whose electron source, NADPH, is generated in the hexose monophosphate shunt. The reduction product, ₂⁻, is further reduced to H₂O₂, which upon the action of myeloperoxidase, oxidizes halide to form reactive chloramines and hypochlorous acid. The elusive hydroxyl radical, or kindred species, also appears as a product of the burst, but this chemistry has not been elucidated. NADPH-oxidase is a complex activity, comprised of at least two components: a low potential b cytochrome and a flavoprotein. Partial characterization and isolation of this electron transport system has been accomplished and serves as an intense focus of current research. The recent demonstration that the oxidase may be activated in a broken cell preparation should not only define mechanisms of burst activation, but this methodology should provide a powerful approach towards identifying the components of the NADPH-oxidase apparatus.

Although the free radical theory of aging was proposed several decades ago the involvement of radicals in the aging process remains obscure. Considerable progress has been made in detecting oxygen free radicals in biological environments and such radicals are now known to be generated during a variety of metabolic processes. The failure to achieve substantial lifespan extensions with antioxidants casts doubt on the validity of the theory as originally formulated. Further doubts about the theory arise from studies with cultured cell aging models, which fail to exhibit an expected sensitivity to the oxygen concentration in their growth environments. Only one nutritional manipulation, caloric restriction, is known to exert substantial life-extending effects; however its relationship to free radicals has not been resolved. Thus, present knowledge does not argue for a predominant role of free radicals in aging. However, compelling evidence exists for the involvement of free radicals in life-shortening diseases, including autoimmunity, cancer, atherosclerosis, and Parkinson's disease. Further studies of the effects of normally-occurring free radicals are warranted; quantitative data on damage associated with these species may reveal that previous analyses failed to identify critical cellular targets.

The Marcus theory for outer-sphere (non-bonded) electron transfer reactions is presented. In addition, it is applied to the problem of identifying compounds capable of generating radical ions and/or radicals $\text{via}$ fast electron transfer to or from redox proteins. The use of the Marcus treatment is illustrated by several examples involving different types of xenobiotics.