Free radicals and antioxidants


ROS reactive oxygen species

Various normal reactions and functions generate reactive oxygen species (ROS) and other compounds that are characterized by their high potential for causing oxidative damage to the body's DNA. proteins, membranes, and other components. Several of these compounds arc called free radicals because they contain an unpaired electron-Free radicals have a strong propensity to donate their unpaired electron to another compound or to abstract an electron from elsewhere to complement their own unpaired one. Their high and unspecilic reactivity gives them the power to modify most biological macromolecules and disrupt their structure. These relentless attacks are thought to be a major cause for progressive functional decline with aging (e.g. macular degeneration) anil major chronic diseases of adulthood, including cardiovascular disease, cancer, and rheumatoid arthritis. Nonetheless, some ROS are of \ ital importance for signaling and immune defense, and their elimination would probably be harmful. Several enzyme-catalyzed reactions detoxify ROS and various redox-active metabolites provide additional protection. Adequate availability of diet-derived cofactors, such as vitamins C and selenium, zinc, and manganese, maintains the body's natural antioxidant protection. Foods contain a wide range of additional antioxidants that may have beneficial properties. The potential for inadvertent suppression of vital ROS functions, their llunjbuuk of Nutrient Mtfabo1t»m Copyright C 200.1 Elsevier Ltd

ISBN: (>-12-117762-X All rights nfrcpradiietiun in uny form reserved conversion into free radical metabolites, or activities unrelated to their free-radical fighting properties makes intake of large amounts of exogenous antioxidants a double-edged sword. There is unequivocal evidence that at least some antioxidants, such a> beta-carotene and vitamin E. cause harm when taken as high-dosed supplements for a long lime (Albanes et al., 1995). The same compounds protect against atherosclerosis. cancer and other diseases when consumed in modest quantities from a mixed diet rich tn fruits and vegetables.

Types of oxygen free radicals

ROS are to a large extent the non-stoichiometric byproducts of oxidative phosphorylation. When an electron in the respiratory chain moves to oxygen instead of the next acceptor in line, superoxide anion forms (Cadenas and Davies. 20011), A healthy 70 kg man may be expected to generate about 190-3X0 mmol per day, based on the assumption that 1 2"» of the oxygen consumption produces superoxide anion. An additional mechanism for the production of ROS during oxidative phosphorylation occurs with the transfer of less than the required four electrons to oxygen, flic transfer of only one electron generates superoxide anion, two added electrons yield hydrogen peroxide, and three electrons give rise to hydroxyl radical l*OH). Partial disruption of oxidative phosphorylation by alcohol (Bailey and Cunningham. 2002), mcthamphctaminc (Virmani et ill.. 2002). other compounds, illness or genetic variants increases the production of ROS byproducts.

Another major source of ROS is the breakdown of purine nucleotides (adenosine and guanosine) in peroxisomes. The final conversion to uric acid by xanthine oxidase (ECl.l .3.22. contains FAD. iron, and molybdenum) produces hydrogen peroxide. The typical dailv production of about 400 XOOmg uric acid generates 2 5 mmol H2Oj. Many other peroxisomal reactions also generate hydrogen peroxide. Several NADU NADPII oxidases, lipoxygenases, eyclooxygenase, and P-450 monooxygenases in other cellular compartments also contribute to ROS production.

Ozone (Oj) is an inhaled ROS that readily reaches any tissue along with normal oxygen At moderate levels around 5Uppb about I jjanol is inhaled per day. This amount adds little to total oxidant burden, but local effects at the point of first contact, i.e. respiratory mucosa and lung alveoli, are much more significant.

Sunlight and other types of radiation are potent inducers of ROS production. Ultraviolet light is particularly damaging when acting on skin with little protection from pigments or sunscreen or on the retina of the eye.

One of the most harmful ROS. the hydroxyl radical, is mainly generated during metal-catalyzed secondary reactions (Fenton reactions). Superoxide anion transfers its excess electron to a metal ion, usually iron or copper (reaction equation 1). The reduced metal ion can then abstract an electron again from hydrogen peroxide and cleave it into a hydroxyl ion and a hydroxyl radical (reaction equation 2). It is this reaction that makes unbound iron and copper so toxic even at micromolar concentrations, particularly in the presence of hydrogen peroxide.

O, 4 Fe3 * —* Oi + Fe;' H.O> + Fe^ 'OH +OH + Fe3"

{reaction equation 1) (reaction equation 2}

labi* 9.1 Fie« radicak. compound* with an unpaired electron, Are common

Superoxide anion (Oj ) Ojwrtt (0,)

Hydrogen pcronde ( HjOj} Singlet oxygen ('0,) HydroJtyl radiiatCOH) Tocopherol radical Sem ide hydroasco rba re Nimc oxide (NO*) Peroxintirite (ONOO ) Fatty acid hydroxyperoxides Tryptophan radical (*Trp) Tyrosine (TyrO*)

The signaling compound nitric oxide (NO*), which is produced from arginine, can combine with a superoxide anion and Form the highly reactive peroxynitnte (reaction equation 3).

Protonation of peroxynitnte forms the unstable intermediate IIONOO. which rapidly decomposes with the release of a hydroxyl radical.

The reaction of primary ROS with additional susceptible targets can convert these into radicals. Important examples include tryptophan (*Trp). tyrosine (TyrO*), and bilirubin radicals. Polyunsaturated fatty acids are particularly susceptible targets. Their oxidation initiates a rapidly cascading chain reaction because each radical generates two new oxidized fatly acid radicals. The metabolites of oxidized fatty acid including 4-hydroxy-2,3-trans-noncnal (HNE), erotonaldehyde. and malondiatdehydc, are highly reactive compounds that can crosslink proteins and engage in other harmful reactions. The major antioxidants also come out of each encounter with ROS as free radicals that have to be detoxilied by auxiliary reactions as described below. This is the case with vitamin F (toeopheroxyl radical), ascorbate (semidehydroascorbate), and llavonoids.

Some commonly consumed foods, including coffee (Ruiz-Laguna and Pueyo, 1999), fried foods (Wilson eta!,, 2(102), and even wine (Rossetto et a!., 2(H) 1). can be a source of exogenous ROS and other free radical species.

Physiological functions

The notion thai certain ROS play important roles in normal body function is gaining momentum. ROS provide signals thai can trigger mitogen-activated protein kinases (Klotz etal,. 2002), modulate the adhesion of neutrophils to target sites and initiate their activation (Guo and Ward 2002), and stimulate hormonal responses (Hsieh et a!.. 2(M)2).

The production of ROS is ciearly regulated in some instances. A key step of programmed cell death (apoptosis) is the inactivation of mitochondrial cytochrome c for the enhanced production of ROS (Moncada and Erusalimsky, 2002), The inactivation can be spontaneous (indicating defective cell function) or the result of a regulatory event (to initiate removal of a targeted cell). The ensuing high level of ROS then contributes to the franmeniation of the cell's DNA and its ultimate demise.

ROS also enable immune cells to destroy and remove pathogens. Before macrophages and other immune eells engulf bacteria, they can disrupt them with a directed stream of corrosive reaeLints. This oxidative blast uses ROS in addition to hypochlorous acid and other chemicals (Vazquez-Torres et a!.. 2000). An NADPII oxidase (phagocyte oxidase. no EC number assigned) uses FAD and cytochrome b (55K> to transler a single electron to oxygen and generate superoxide anion (Seguchi and Kobayashi. 2002). The nitric oxide produced by nitric oxide synthase (EC; contains heme and uses tetrahydrobioptenn as a cofactor) can then be combined by the lysosomal heme-en/yme myeloperoxidase [ECU 1.1.7) with superoxide to generate peroxynitrite (Eiserich etid., 2002). Superoxide also drives the production of hydrogen peroxide by superoxide dismutase (EC1.15.1.1}.

ROS-induced damage

The main characteristic of ROS is their high reactivity with low specificity. They oxidize and crosslink proteins, fragment DNA and alter its bases, and disrupt membranes by oxidizing their fatty acids.

DNA and RNA: The molecular structures of more than seventy ROS-induced DNA modifications have been identified (Pouget el at„ 2002), Among the most common lesions are 8-oxo-7.K-dihydro-2'-deoxyguanosine (8-oxo-dGuo), 5-formyl-2'-deoxy-uridine (5-FordUrd), 5-( hydroxy methyl )-2'-deoxyuridine (5-HmdUrd), and 5,6-dihydroxy-5v6-dihydrothymidine (dThdGly),

Polyunsaturated fatty acids: Tlie changes to cholesteryllinoleate of LDL exposed to monocytes should illustrate oxidative damage occurring with exposure to ROS. In our scenario the oxidative blast of activated monocytes has released superoxide and hydrogen peroxide and a Fenton reaction in the presence of free ionic iron has generated hydroxyl radicals. Lipid oxidation starts with the abstraction of a proton from carbon 11 between the two double bonds, but without its electron. This converts the hydroxy! radical into water, but leaves the cholesteryllinoleate with a supernumerary electron at carbon 11. Shift of the 12,13 double bond and movement of the extra electron to carbon 13 forms an unstable conjugated dienc. The shift can also occur in the other direction




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