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C holestery I -13- hydrox y-octa-c9,111-diene o-c

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C holestery I -13- hydrox y-octa-c9,111-diene

Figure "J.2 Oxidative damage to poiyuns.it urn led lipids tends to spread

Mechanisms of antioxidant action

Mela! ion chelation: The formation of ROS is effectively reduced by maintaining iron and copper in tightly bound form that cannot participate in Fen ton-type reactions. The metal-chclating capacity of some food-derived compounds, such as Havonoids, may provide additional protection. The relevance of this effect at the cellular level remains unclear, however.

Enzyme-catalyzed reactions: The body has an elaborate system to protect against ROS. These systems tend to be most active at the sites of greatest ROS release, Catalase (ECU 1.1 ,ii>. which contains both heme and manganese, dissipates hydrogen peroxide in peroxisomes to oxy gen and water. This enzyme w ith its high capacity and low affinity is best suited to detoxify overflow quantities and sudden bursts of hydrogen peroxide. Other enzymes with peroxidase activity have lower capacity, but their high substrate affinity keeps hydrogen peroxide concentrations very low . This group of high affinity peroxidases includes the peroxiredoxins(Prx), which arc closely related heme enzymes.

Different superoxide dismutase (EC1.15.1.1 ) isoenzymes in cytosol and the extracellular space convert superoxide radicals to hydrogen peroxide (reaction equation 4). AH isoenzymes contain copper and a second transition metal. The isoenzyme in mitochondria contains manganese, the ones in cytosol and extracellular fluids contain zinc or iron.

Another high-capacity free radical scavenger in extracellular fluid is the copper-enzyme ferroxidase (ceruloplasmin, iron ( 11 ):oxygen oxidoreductase. EC1.I6..1,1 ).

Thioredoxin reductase (EC 1.6.4.5) is a ubiquitous NADPH-dependent selenoen/yme in cytosol that reduces both dehydroascorbate and the scm¡deitydroascorbate radical to ascorbate (May et al1998).

A different protective strategy seeks to remedy the damage. Four different selenium-containing glutathione peroxidases (EC1. 11.1.9) with distinct tissue distributions and activity profiles use glutathione (GSH) for the reduction of peroxides of free fatty acids and other lipids. Another example is the activity of arylestemse (paraoxonase I, PONI. EC3.1.1.2) in high-density lipoprotein (HDL). This enzyme cleaves the fatty aldehydes from damaged phospholipids and releases them Irom the lipoprotein particle for further metabolic treatment in the liver and other tissues (Ahmed et al., 200! ). Antioxidants: The body uses both fat-soluble and water-soluble compounds to reach all cellular compartments.

Tibi« 9.2 Anuokidaot enzymes

Catalase (EC1.I1.5.6. heme)

Superoxide dismutase (EC 1,15.1.1, iron, manganese, zinc) Peroxidase (EC 1.11.1.7. heme) Glutathione peroxidases (EC!, 11.1.9, selenium) Thioredoxin reductase (EC1.6.4.5, selenium)

Arylcsteraw (EC3 1,1.2)

Ascorbalc

Thiorcdoxin

Lipoate

Tm r,i hydro b iopt rrrn Unr acid

Phenols. flavortoids/isoflavortei

Vitamin E

Ubiquinone

Carotenoids

Conjugal ttil lino Ira' acid

Protein disulfides

Melatonin

Ascorbalc

Thiorcdoxin

Lipoate

Tm r,i hydro b iopt rrrn Unr acid

Phenols. flavortoids/isoflavortei

Vitamin E

Ubiquinone

Carotenoids

Conjugal ttil lino Ira' acid

Protein disulfides

Melatonin

The essential nutrient ascorbate is a particularly versatile antioxidant, because it can quench radicals that have one or two excess electrons. The systems for the regeneration of the oxidized forms include NADH-dependent monodehydroaseorbate reductase (EC1.6.5.4), thioredoxin reductase (ECL6.4.5). and an NADH-dependent dehydroascorbate-reducing transporter in erythrocytes (May et al.. ILWK) Thioredoxin is a small peptide with two redox-active cysteines that potently quenches singlet oxygen and hydroxy I radicals. The oxidation of its cysteines reduces oxidants or oxidized compounds. It also detoxifies hydrogen peroxide in conjunction with a group of enzymes, the peroxiredoxins. Thioredoxin reductase (EC1.6.4.5) uses NADU to rapidly regenerate the oxidized thioredoxin. Lipoate, tetrahydrobiopterin, uric acid phenols, flavonoids ami isollavones, additional protein disulfides, and possibly melatonin add to the mix of water-soluble antioxidants.

Vitamin 1- is particularly important for antioxidant protection in lipoproteins, membranes, and other lipophilic environments Since ihe interaction of R< )S with vitamin E generates the tocopheroxyl radical, the net effectiveness depends on adequate availability of ascorbate and other co-antioxidants for regeneration (Terentis el al.. 2002). Ubiquinone, and tetrahydrobiopterin. have considerable antioxidant potential unrelated to their function as enzyme cofactors. In addition to these endogenous metabolites, a wide range of food-derived compounds is known to provide additional protection. Hundreds of carotenoids from fruits and vegetables increase the resistance of tissues to the harmful effects of ROS.

References

Ahmed Z. Ravandi A, MaguireGF. Emili A, Dntganov D. La Du UN. Kuksis A,Connelly PW. Apolipoprotein A-l promotes the formation of phosphatidylcholine core aldehydes that are hydroiy/ed by paraoxonase (PON-1) during high intensity lipoprotein oxidation with a peroxvniirite donor. J Hint Chew 2001:276:24473 HI Atbancs D. I leinonen OP. Iluttunen IK.Taylor PR. Virtamo J. Edwards UK. I laapakoski J. R&utalahti M. Hartman AM. Palmgren J. Effects of alpha-toeophern! and heta-carotene supplements on cancer incidence in the Alpha-Toeopherol Beta-Carotene Cancer Prevention Study, Am J Clin Nutr 1995:62:1427S-1430S Bailey SM, Cunningham CC. Contribution of mitochondria to oxidative stress associated with alcoholic liver disease. Free Had Bio! Med 2002;32: II 16 Cadenas E. Davics KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Rad Biol Med 2000:29:222 30

Eiscrich JP. Baldus S, Bren mm ML. Ma W. Zhang C, Tousson A. Castro L. Lusts AJ. Nausee!' WM, White LR, Freeman BA. Myeloperoxidase, a leukocytic derived vascular NO oxidase. Science2002;296:2391 4 Folcik VA, ( athcart Mk. Predominance of esterilied hydroperoxy-lirtoleic aeid in human monocyte-oxidized LDL. J Lip Res 1994;35:1570-82 Ouo RF. Ward PA. Mediators and regulation of neutrophil accumulation in inflammatory responses in lung: insights from the Igti immune complex system. Five Rad Bint Med 2002:33:303 10

HsiehTJ. /hang SL. Filep JO, Tang SS, Ingelfinger JR. Chan JS. High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular eells. Endocrinol 2002:143:2975 85 klotz LO, Schroeder P, Sies H. Peroxynitrite signaling: receptor tyrosine kinases and activation of stress-responsive pathways. Free Rad Rad Med 2002:33:737 43 May JM. Cobb CE, Mendiralta S. Hill kli. Burk RK Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase../ Bud Chem 199(t,*273:23039 45 Moneada S. Erusalimsky JÜ. Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nature Rev Mol Cell Biol 2002;3:214-20 Pouget JP. Frelon S, Ravanat JL. Testard I. Odin F. Cadet J. Formation of modified DNA bases in cells exposed either to gamma radiation or to high-i ET particles, Rad Res 2002;157:589-95

Rossetto M. Viancllo K Rign A. Vrhovsck U, Mattivi F. Scarpa M Stable free radicals as ubiquitous components of red wines. Free Rad Res 200l;35:933 9 Ruiz-Laguna J, Pueyo C. Hydrogen peroxide and coffee induce G:C —» T:A transversions in the lacl gene of cat a lase-defective Escherichia coli. Mutagenesis 1999; 14:95 102 Scguchi H, kobayashi T Study ofNADPH oxidase-activated sites in human neutrophils.

./Electron Microsc 2002:51:87-91 Tcrcntis AC, Thomas SR. Burr JA, Liebler DC. Stocket R, Vitamin E oxidation in human atherosclerotic lesions, C/re Res 2002;90:333 9 Vazquez-torres A. Jones-Carson J. Mastroedi P. Ischiropoulos H. Fang FC. Antimicrobial actions of the NADPI1 phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro, J E\p Med 2000:192:227 36 Virmani A. Gaetani F, Imam S. Binienda Z. Ali S. The protective role of L-earnitine against neurotoxicity evoked by drug of abuse, meth amphetamine, could be related to mitochondrial dysfunction. Inn NY Acad Sei 2002;965:225-32 Wilson R. Lyatl K. Smyth L, Fertile CE, Riemersnia RA. Dietary hydroxy fatty acids are absorbed in humans: implications lor the measurement of "oxidative siress" in vivo. Free Rad Bio! Med 2002:32:162 8

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