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FREE RADICAL FORMATION Atoms are most stable in the ground state.

An atom is considered to be "ground" when every electron in the outermost shell has a complimentary electron that spins in the opposite direction. By definition a free radical is any atom (e.g. oxygen, nitrogen) with at least one unpaired electron in the outermost shell, and is capable of independent existence (1 ). A free radical is easily formed when a covalent bond between entities is bro!en and one electron remains with each newly formed atom (1 ). "ree radicals are highly reactive due to the presence of unpaired electron(s). #he following literature review addresses only radicals with an oxygen center. Any free radical involving oxygen can be referred to as reactive oxygen species ($%&). %xygen centered free radicals contain two unpaired electrons in the outer shell. 'hen free radicals steal an electron from a surrounding compound or molecule a new free radical is formed in its place. (n turn the newly formed radical then loo!s to return to its ground state by stealing electrons with antiparallel spins from cellular structures or molecules. #hus the chain reaction continues and can be "thousand of events long." ()). #he electron transport chain (*#+), which is found in the inner mitochondrial membrane, utili,es oxygen to generate energy in the form of adenosine triphosphate (A#-). %xygen acts as the terminal electron acceptor within the *#+. #he literature suggests that anywhere from . to /0 (11) of the total oxygen inta!e during both rest and exercise have the ability to form the highly damaging superoxide radical via electron escape. 2uring exercise oxygen consumption increases 13 to .3 fold to /4)3 ml5!g5min. (n turn, electron escape from the *#+ is further enhanced. #hus, when calculated, .6 to ./ ml5!g5min of the total oxygen inta!e during exercise has the ability to form free radicals (1). *lectrons appear to escape from the *#& at the ubi7unone4cytochrome c level (11). PEROXIDATION -olyunsaturated fatty acids (-8"As) are abundant in cellular membranes and in low4density lipoproteins (929) (1). #he -8"As allow for fluidity of cellular membranes. A free radical prefers to steal electrons from the lipid membrane of a cell, initiating a free radical attac! on the cell !nown as lipid peroxidation. $eactive oxygen species target the carbon4carbon double bond of polyunsaturated fatty acids. #he double bond on the carbon wea!ens the carbon4hydrogen bond allowing for easy dissociation of the hydrogen by a free radical. A free radical will steal the single electron from the hydrogen associated with the carbon at the double bond. (n turn this leaves the carbon with an unpaired electron and hence becomes a free radical. (n an effort to stabili,e the carbon4centered free radical molecular rearrangement occurs. #he newly arranged molecule is called a con:ugated diene (+2). #he +2 then very easily reacts with oxygen to form a proxy radical. #he proxy radical steals an electron from another lipid molecule in a process called propagation. #his process then continues in a chain reaction (;) TYPES OF FREE RADICALS

#here are numerous types of free radicals that can be formed within the body. #his web site is only concerned with the oxygen centered free radicals or $%&. #he most common $%& include< the superoxide anion (%.4), the hydroxyl radical (%= >), singlet oxygen (1%. ), and hydrogen peroxide (=.%.) &uperoxide anions are formed when oxygen (%.) ac7uires an additional electron, leaving the molecule with only one unpaired electron. 'ithin the mitochondria %.4 > is continuously being formed. #he rate of formation depends on the amount of oxygen flowing through the mitochondria at any given time. =ydroxyl radicals are short4lived, but the most damaging radicals within the body. #his type of free radical can be formed from %.4 and =.%. via the =arber4'eiss reaction. #he interaction of copper or iron and =.%. also produce %= > as first observed by "enton. #hese reactions are significant as the substrates are found within the body and could easily interact (;). =ydrogen peroxide is produced in vivo by many reactions. =ydrogen peroxide is uni7ue in that it can be converted to the highly damaging hydroxyl radical or be cataly,ed and excreted harmlessly as water. ?lutathione peroxidase is essential for the conversion of glutathione to oxidi,ed glutathione, during which =.%. is converted to water (.). (f =.%. is not converted into water 1%. is formed. &inglet oxygen is not a free radical, but can be formed during radical reactions and also cause further reactions. &inglet oxygen violates =und@s rule of electron filling in that it has eight outer electrons existing in pairs leaving one orbital of the same energy level empty. 'hen oxygen is energetically excited one of the electrons can :ump to empty orbital creating unpaired electrons (1 ). &inglet oxygen can then transfer the energy to a new molecule and act as a catalyst for free radical formation. #he molecule can also interact with other molecules leading to the formation of a new free radical. CATALYSTS All transition metals, with the exception of copper contain one electron in their outermost shell and can be considered free radicals. +opper has a full outer shell, but loses and gains electrons very easily ma!ing itself a free radical (;). (n addition iron has the ability to gain and lose electrons (i.e. ("e.AB"e A) very easily. #his property ma!es iron and copper two common catalysts of oxidation reactions. (ron is ma:or component of red blood cells ($B+). A possible hypothesis is that the stress encountered during may brea! down $B+ releasing free iron. #he release of iron can be detrimental to cellular membranes because of the pro4oxidation effects it can have. Cinc only exists in one valence (Cn.A) and does not cataly,e free radical formation. Cinc may actually act to stop radical formation by displacing those metals that do have more than one valence. MEASUREMENT OF FREE RADICALS "ree radicals have a very short half4life, which ma!es them very hard to measure in the laboratory. Dultiple methods of measurement are available today, each with their own benefits and limits. $adicals can be measured using electron spin resonance and spin trapping methods. #he methods are both very sophisticated and can trap even the shortest4lived free radical.

*xogenous compounds with a high affinity for free radicals (i.e. xenobiotics) are utili,ed in the spin techni7ues. #he compound and radical together form a stable entity that can be easily measured. #his indirect approach has been termed "fingerprinting." (1.). =owever, this method is not 1330 accurate. &pin4trapping collection techni7ues have poor sensitivity, which can s!ew results (1) A commonly used alternate approach measures mar!ers of free radicals rather than the actual radical. #hese mar!ers of oxidative stress are measured using a variety of different assays. #hese assays are described below. 'hen a fatty acid is peroxidi,ed it is bro!en down into aldehydes, which are excreted. Aldehydes such as thiobarbituric acid reacting substances (#BA$&) have been widely accepted as a general mar!er of free radical production ( ). #he most commonly measured #BA$& is malondialdehyde (D2A) (1 ). #he #BA test has been challenged because of its lac! of specificity, sensitivity, and reproducibility. #he use of li7uid chromatography instead spectrophotometer techni7ues help reduce these errors (1/). (n addition, the test seems to wor! best when applied to membrane systems such as microsomes (E). ?ases such as pentane and ethane are also created as lipid peroxidation occurs. #hese gases are expired and commonly measured during free radical research (1 ). 2illard et al. (6) was one of the first to determine that expired pentane increased as F%. max increased. Ganter et al. (11) has reported that serum D2A levels correlated closely with blood levels of creatine !inase, an indicator of muscle damage. 9astly, con:ugated dienes (+2) are often measured as indicators of free radical production. %xidation of unsaturated fatty acids results in the formation of +2. #he +2 formed are measured and provide a mar!er of the early stages of lipid peroxidation (;). A newly developed techni7ue for measuring free radical production shows promise in producing more valid results. #he techni7ue uses monoclonal antibodies and may prove to be the most accurate measurement of free radicals. =owever, until further more reliable techni7ues are established it is generally accepted that two or more assays be utili,ed whenever possible to enhance validity (;) PHYSIOLOGICAL EFFECTS 8nder normal conditions (at rest) the antioxidant defense system within the body can easily handle free radicals that are produced. 2uring times of increased oxygen flux (i.e. exercise) free radical production may exceed that of removal ultimately resulting in lipid peroxidation. "ree radicals have been implicated as playing a role in the etiology of cardiovascular disease, cancer, Al,heimer@s disease, and -ar!inson@s disease. 'hile worthy of a discussion these conditions are not the focus of the current literature review. #his literature review will only examine the current literature addressing the relationship between free radicals and exercise, which is introduced below. #he driving force behind these topics is lipid peroxidation. By preventing or controlling lipid peroxidation the concomitant effects discussed below would be better controlled. REQUIREMENT %xygen consumption greatly increases during exercise, which leads to

increased free radical production. #he body counters the increase in free radical production through the antioxidant defense system. 'hen free radical production exceeds clearance oxidative damage occurs. "ree radicals formed during chronic exercise may exceed the protective capacity of the antioxidant defense system, thereby ma!ing the body more immune to disease and in:ury. #herefore the need for antioxidant supplementation is discussed. FATIGUE A free radical attac! on a membrane usually damages a cell to the point that it must be removed by the immune system. (f free radical formation and attac! are not controlled within the muscle during exercise a large 7uantity of muscle could easily be damaged. 2amaged muscle could in turn inhibit performance by the induction of fatigue. #he role individual antioxidants have in inhibiting this damage has been addressed within the review of the four antioxidants that follows. RECOVERY %ne of the first steps in recovery from exercise induced muscle damage is an acute inflammatory response at the site of muscle damage. "ree radicals are commonly associated with the inflammatory response and are hypothesi,ed to be greatest twenty4four hours after completion of a strenuous exercise session. (f this theory were valid then antioxidants would play a ma:or role in helping prevent this damage. =owever, if antioxidant defense systems are inade7uate or not elevated during the post4exercise infiltration period free radicals could further damage muscle beyond that ac7uired during exercise. #his in turn would increase the time needed to recover from an exercise bout. IMPORTANCE OF FREE RADICALS #his section has focused only on the negatives associated with free radical production. =owever, free radicals are naturally produced by some systems within the body and have beneficial effects that cannot be overloo!ed. #he immune system is the main body system that utili,es free radicals. "oreign invaders or damaged tissue is mar!ed with free radicals by the immune system. #his allows for determination of which tissue need to be removed from the body. Because of this some 7uestion the need for antioxidant supplementation, as they believe supplementation can actually decrease the effectiveness of the immune system ANTIOXIDANT DEFENSES Antioxidant means "against oxidation." Antioxidants wor! to protect lipids from peroxidation by radicals. Antioxidants are effective because they are willing to give up their own electrons to free radicals. 'hen a free radical gains the electron from an antioxidant it no longer needs to attac! the cell and the chain reaction of oxidation is bro!en (1). After donating an electron an antioxidant becomes a free radical by definition. Antioxidants in this state are not harmful because they have the ability to accommodate the change in electrons

without becoming reactive. #he human body has an elaborate antioxidant defense system. Antioxidants are manufactured within the body and can also be extracted from the food humans eat such as fruits, vegetables, seeds, nuts, meats, and oil. #here are two lines of antioxidant defense within the cell. #he first line, found in the fat4soluble cellular membrane consists of vitamin *, beta4carotene, and coen,yme H (13). %f these, vitamin * is considered the most potent chain brea!ing antioxidant within the membrane of the cell. (nside the cell water soluble antioxidant scavengers are present. #hese include vitamin +, glutathione peroxidase, superoxide dismutase (&2), and catalase (1). %nly those antioxidants that are commonly supplemented (vitamins A, +, * and the mineral selenium) are addressed in the literature review that follows. REFERENCES 1.Acworth, (.I., and B. Bailey. $eactive %xygen &pecies. (n< #he handboo! of oxidative metabolism. Dassachusetts< *&A (nc., 1;;), p. 141 to 141. 2. Alessio, =.D., and *.$. Blasi. -hysical activity as a natural antioxidant booster and its effect on a healthy lifestyle. $es. H. *xerc. &port. 6E (1)< .;.4 3., 1;;). JAbstractK 3. +lar!son -. D. Antioxidants and physical performance. +rit.$ev. "ood &ci. Iutr. /< 1 14111, 1;;/. JAbstractK 4. 2e!!ers, L. +., 9. L. -. van 2oornen, and =an +. ?. Gemper. #he $ole of Antioxidant Fitamins and *n,ymes in the -revention of *xercise4 (nduced Duscle 2amage. &ports Ded .1< .1 4. E, 1;;6. JAbstractK /.2el Dastero, $.". An approach to free radicals in medicine an biology. Acta. -hyiol. &cand. 1;.< 1/ 416E, 1;E3. 6. 2illard, +.L., $.*. 9itov, '.D. &avin, *.*. 2umelin, and A.9. #appel. *ffects of exercise, vitamin *, and o,one on pulmonary function and lipid peroxidation. L. Appl. -hysiol. 1/< ;.), 1;)E. JAbstractK 7. ?oldfarb, A. =. Iutritional antioxidants as therapeutic and preventive modalities in exercise4induced muscle damage. +an. L. Appl. -hysiol. .1< .1;4.66, 1;;;. JAbstractK 8. =alliwell, B., and &. +hirico. 9ipid peroxidation< (ts mechanism, measurement, and signficance. Am. L. +lin. Iutr. /)< )1/&4)./&, 1;; . JAbstractK ;.=alliwell, B., and L.D.+. ?utteridge. #he chemistry of oxygen radicals and other oxygen4derived species. (n< "ree $adicals in Biology and Dedicine. Iew Mor!< %xford 8niversity -ress, 1;E/, p. .3461. 10. Gac,mars!i, D., L. 'o:icic!i, 9. &amochowiee, #. 2ut!iewic,, and C. &ych. #he influence of exogenous antioxidants and physical exercise on some parameters associated with production and removal of free radicals. -harma,ie /1< 3 4 36, 1;;;. JAbstractK 11. Ganter, D.D., ?.$. 9esmes, 9.A. Gamins!y, L. 9a=am4&aeger, and I.2. Ie7uin. &erum creatine !inase and lactate dehydrogenase changes following an eighty4!ilometer race. *ur. L. Appl. -hsyiol. /)< 6346/, 1;EE. JAbstractK 12. Garlsson L. *xercise, muscle metabolism and the antioxidant defense. 'orld $ev Iutr 2iet. E.<E14133, 1;;). JAbstractK

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Garlsson, L. (ntroduction to Iutraology and $adical "ormation. (n< Antioxidants and *xercise. (llinois< =uman Ginetics -ress, 1;;), p. 14 11 . &:odin, #., M.=. 'esting, and ".&. Apple. Biochemical mechanisms for oxygen free radical formation during exercise. &ports Ded. 13< . 64 ./1, 1;;3. JAbstractK 'ong, &.=.M., L.A. Gnight, &.D. =opfer, %. Caharia, +.I. 9each, and ".'. &underman. 9ipoperoxides in plasma as measured by li7uid4 chromatographic separation of malondialdehyde4thiobarbituric acid adduct. +lin. +hem. (.)< .114..3, 1;E). JAbstractK Acworth, (.I., and B. Bailey. $eactive %xygen &pecies. (n< #he handboo! of oxidative metabolism. Dassachusetts< *&A (nc., 1;;), p. 141 to 141. Alessio, =.D., and *.$. Blasi. -hysical activity as a natural antioxidant booster and its effect on a healthy lifestyle. $es. H. *xerc. &port. 6E (1)< .;.4 3., 1;;). JAbstractK +lar!son -. D. Antioxidants and physical performance. +rit.$ev. "ood &ci. Iutr. /< 1 14111, 1;;/. JAbstractK 2e!!ers, L. +., 9. L. -. van 2oornen, and =an +. ?. Gemper. #he $ole of Antioxidant Fitamins and *n,ymes in the -revention of *xercise4 (nduced Duscle 2amage. &ports Ded .1< .1 4. E, 1;;6. JAbstractK 2el Dastero, $.". An approach to free radicals in medicine an biology. Acta. -hyiol. &cand. 1;.< 1/ 416E, 1;E3. 2illard, +.L., $.*. 9itov, '.D. &avin, *.*. 2umelin, and A.9. #appel. *ffects of exercise, vitamin *, and o,one on pulmonary function and lipid peroxidation. L. Appl. -hysiol. 1/< ;.), 1;)E. JAbstractK ?oldfarb, A. =. Iutritional antioxidants as therapeutic and preventive modalities in exercise4induced muscle damage. +an. L. Appl. -hysiol. .1< .1;4.66, 1;;;. JAbstractK =alliwell, B., and &. +hirico. 9ipid peroxidation< (ts mechanism, measurement, and signficance. Am. L. +lin. Iutr. /)< )1/&4)./&, 1;; . JAbstractK =alliwell, B., and L.D.+. ?utteridge. #he chemistry of oxygen radicals and other oxygen4derived species. (n< "ree $adicals in Biology and Dedicine. Iew Mor!< %xford 8niversity -ress, 1;E/, p. .3461. Gac,mars!i, D., L. 'o:icic!i, 9. &amochowiee, #. 2ut!iewic,, and C. &ych. #he influence of exogenous antioxidants and physical exercise on some parameters associated with production and removal of free radicals. -harma,ie /1< 3 4 36, 1;;;. JAbstractK Ganter, D.D., ?.$. 9esmes, 9.A. Gamins!y, L. 9a=am4&aeger, and I.2. Ie7uin. &erum creatine !inase and lactate dehydrogenase changes following an eighty4!ilometer race. *ur. L. Appl. -hsyiol. /)< 6346/, 1;EE. JAbstractK Garlsson L. *xercise, muscle metabolism and the antioxidant defense. 'orld $ev Iutr 2iet. E.<E14133, 1;;). JAbstractK Garlsson, L. (ntroduction to Iutraology and $adical "ormation. (n< Antioxidants and *xercise. (llinois< =uman Ginetics -ress, 1;;), p. 14 11 . &:odin, #., M.=. 'esting, and ".&. Apple. Biochemical mechanisms for oxygen free radical formation during exercise. &ports Ded. 13< . 64

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./1, 1;;3. JAbstractK 'ong, &.=.M., L.A. Gnight, &.D. =opfer, %. Caharia, +.I. 9each, and ".'. &underman. 9ipoperoxides in plasma as measured by li7uid4 chromatographic separation of malondialdehyde4thiobarbituric acid adduct. +lin. +hem. (.)< .114..3, 1;E). JAbstractK