Combined effects of coenzyme Q 10 and Vitamin E in cadmium induced alterations of antioxidant defense system in the rat heart

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Combined effects of coenzyme Q 10 and Vitamin E in cadmium induced alterations of antioxidant defense system in the rat heart
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  Environmental Toxicology and Pharmacology 22 (2006) 219–224 Combined effects of coenzyme Q 10  and Vitamin E in cadmium inducedalterations of antioxidant defense system in the rat heart Branka I. Ognjanovi´c a , ∗ , Sneˇzana D. Markovi´c a , Sladjan Z. Pavlovi´c b ,Radoslav V. ˇZiki´c a , Andraˇs ˇS. ˇStajn a , Zorica S. Saiˇci´c b a  Institute of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovi´ ca 12, P.O. Box 60, 34000 Kragujevac, Serbia and Montenegro b  Institute for Biological Research “Siniˇ sa Stankovi´ c”, Department of Physiology, Belgrade, Serbia and Montenegro Received 25 October 2005; accepted 24 March 2006Available online 18 May 2006 Abstract Our study investigated the possible protective effects of coenzyme Q 10  (CoQ 10 ) and Vitamin E (Vit E) alone or in combination against cadmium(Cd) induced alterations of antioxidant defense system in the rat heart. Male Wistar rats were injected with a single dose of CdCl 2  (0.4mg Cd/kgBW i.p.), CoQ 10  (20mg CoQ 10  /kg BW i.m.) and Vit E (20IU Vit E/kg BW i.m.), alone or in combination. Acute intoxication of rats with Cd werefollowed by significantly increased activity of antioxidant defense enzymes (CuZn SOD, GSH-Px, GST and GR), while the activity of Mn SODwas decreased in the heart. The treatment with Cd significantly decreased Vit C and Vit E concentrations. Treatment with CoQ 10  and Vit E reversedCd-induced alterations of antioxidant defense system. The obtained results support the assumption that CoQ 10  and Vit E functions cooperativelywith endogenous antioxidants and diminished toxic effects of Cd in rat heart.© 2006 Elsevier B.V. All rights reserved. Keywords:  Coenzyme Q 10 ; Vitamin E; Antioxidant defense system; Cadmium; Heart; Rats 1. Introduction Cadmium (Cd) is an ubiquitous, non-essential element thathas recently raised concerns due to its accumulation in the envi-ronment as a result of industrial and agricultural practices. Thetoxicity of Cd as an industrial pollutant a food contaminant andasoneofthemajorcomponentsincigarettesmokehasbeenwellestablished (Stohs and Bagchi, 1995; Waisberg et al., 2003). In the human body, Cd has a biological half-life of more than 20years. All of the above circumstances suggest that Cd intake inhumans will increase in the future (Stohs et al., 2001).Cd shows different mechanisms of toxicity under differentexperimental conditions and in various species (Shukla andChandra, 1989; Stohs and Bagchi, 1995; ˇZiki´c et al., 1996).The molecular mechanism responsible for the toxic effects of Cd is far from being completely understood. Suggestion of the type of damage involved in Cd-induced cellular toxicityinclude: interference with antioxidant defense enzymes (Shukla ∗ Corresponding author: Tel.: +381 34 336 223; fax: +381 34 335 040.  E-mail address:  branka@kg.ac.yu (B.I. Ognjanovi´c). et al., 1996), alterations in thiol proteins (Li et al., 1993), inhi- bition of energy metabolism (Kosti´c et al., 1993), alteration inDNA structure (Waisberg et al., 2003) and altered membrane structure/function (Stohs et al., 2001). Since it causes lipid per- oxidation in numerous tissues both in vivo and in vitro (Kosti´cet al., 1993; Ognjanovi´c et al., 1995; Casalino et al., 1997) it hasbeensuggestedthatCdmayinduceoxidativestressbyproducinghydroxyl radicals (O’Brien and Salasinski, 1998), superoxide anion radicals, nitric oxide and hydrogen peroxide (Stohs et al.,2001; Waisberg et al., 2003).Recent studies showed that the increased activity of someantioxidantenzymesmaybetheconsequenceofitsgeneexpres-sion and induction in response to a variety of stimuli includingantioxidants, xenobiotics, metals and UV irradiation (Jaiswal,2004).TheproblemofpreventionandtherapeuticinterventioninCdintoxicationmaybeapproachedintwoways:(1)chelationofCdthat has been localized intracellularly bound to metallothionein(MT) mainly in liver and kidneys after the exposure (Andersen,1999) and (2) free radical scavenging by antioxidants and enzy-matic components of antioxidant defense system (Shaikh et al.,1999; Tandon et al., 2003). 1382-6689/$ – see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.etap.2006.03.008  220  B.I. Ognjanovi´ c et al. / Environmental Toxicology and Pharmacology 22 (2006) 219–224 Two known antioxidants, coenzyme Q 10  (CoQ 10 ) and Vita-min E (Vit E) were also investigated for their potential to reduceCdinducedoxidativestress.CoQorubiquinoneisaredox-activelipoidal substance present in the hydrophobic middle region of the phospholipid bilayer of cellular membranes including thoseof the mitochondria (Beyer, 1994; Ernster and Dallner, 1995).Three main functions are attributed to this lipid depending ondistribution and concentration. It is a redox component of themitochondrial respiratory chain and this electron carrier rolewas considered for a long time to be its only function. However,its broad distribution provides a clue to its additional cellularrole as the only endogenously synthesized lipid-soluble antiox-idant (Ernster and Dallner, 1995). CoQ is highly efficient in preventing lipid, protein and DNA oxidation and it is continu-ously regenerated by intracellular reduction systems (Andr´ee etal., 1998). In some pathologic processes, when tissue CoQ con-tent is decreased it may be advantageous to supplement CoQby dietary administration (Ernster and Dallner, 1995; Ibrahim etal., 2000).Vit E comprises eight naturally occurring fat-soluble vita-mins of which the most predominant, essential and with thehighest biological activity is   -tocopherol (Chen and Tappel,1995). Vit E is a major antioxidant in biological systems actingas a powerful chain-breaking agent through the scavenging of peroxyl radicals (Beyer, 1994; Shi et al., 1999). Vit E termi- nates the chain reaction of lipid peroxidation in membranes andlipoproteins. Thus, a number of studies have been carried out todetermine the protective effects of Vit E in different biologicalmodels of injury (Chen and Tappel, 1995; Ernster and Dallner,1995).Currently, there is considerable interest in the roles of Vit Eand CoQ in the protection of membrane lipids against oxidativestress (Shi et al., 1999). CoQ has been demonstrated to serve the dual functions of an electron carrier/proton translocator inthe respiratory chain and an antioxidant by directly scavengingradicalsorindirectlybyregeneratingVitE(Beyer,1994;Andr´eeet al., 1998).In this study, a possible protective effects of CoQ 10  and/orVit E in combination against Cd-induced alterations enzymaticand non-enzymatic components of antioxidant defense systemsin heart tissue of rats was investigated. 2. Materials and methods 2.1. Chemicals Cadmium chloride (CdCl 2 , 99% pure) was purchased from Aldrich Chemi-cal Co. Nicotinamide adenine dinucleotide phosphate (reduced form; NADPH);reduced (GSH) and oxidized (GSSG) glutathione; 1-chloro-2,4-dinitrobenzene(CDNB); glutathione reductase;  tert  -butyl hydroperoxide ( t  -BOOH); bovineserum albumin; coenzyme Q 10  (CoQ 10 , ubiquinone 10); ascorbic acid; 2,4-dinitrophenyl-hydrazine;VitaminE(  -tocopherolacetate)werepurchasedfromSigma Chemical Co. (St. Louis, MO, U.S.A.). All other chemicals were of thehighest purity commercially available. 2.2. Animal and treatment  Themaleadult Wistaralbino ratsweighing250–280gkepton12-hlight:12-h dark cycles with controlled temperature (20–22 ◦ C) were used. All animalswere housed in individual cages and given a standard diet and tap water ad libi-tum.Thefirstgroupwasusedascontrol.Theratsoftheexperimentalgroupwereinjected (2) i.m. with a single dose of CoQ 10  (20mg/kg body weight) plus Vit E(20IU/kg body weight) in 0.1ml olive oil and sacrificed 48h after injection, (3)i.p. with a single dose of CdCl 2  (0.4mg Cd/kg body weight) in 0.1ml saline andsacrificed24hafterinjection,(4)CoQ 10  +Cd,(5)VitE+Cdand(6)CoQ 10  +VitE+Cd (in above mentioned amounts). Control animals received the equivalentvolume of saline (0.1ml/kg body weight). Above mentioned concentrations andtime points were used according to the well-known literature data (Sarkar etal., 1998; Xu et al., 2005). Every group consisted of eight animals. After thetreatment, the animals were sacrificed by decapitation always between 8:00 and10:00h to avoid any possible cyclic daily variations in antioxidant levels. 2.3. Tissue preparation The heart tissue was dissected, thoroughly washed with ice-cold saline,weighed, minced and homogenized with a Thomas Sci Co. glass homogenizer(Teflon pestle) at 0–4 ◦ C (10% w/v) using 0.25M sucrose, 1mM EDTA and0.05M Tris–HCl solution and pH 7.4. Heart homogenate from both controland treated rats was used for Vit C and Vit E determination. The homogenateswerecentrifuged(90minat100,000 × g ,4 ◦ C)andthesupernatantwasusedforantioxidant enzyme activity assays and for total protein determination. 2.4. Antioxidant enzyme analyses Superoxide dismutase (SOD) activity was determined by the epinephrinemethod (Misra and Fridovich, 1972). This method is based on the measurement of the rate of epinephrine auto-oxidation inhibition by SOD contained in theexaminedsamplesin50mMsodiumcarbonatebuffer,pH10.2,withinthelinearrange of auto-oxidative curve. For the determination of manganese containingSOD(MnSOD)activity,theassaywasconductedafterpreincubationwith8mMKCN. The copper zinc containing SOD (CuZn SOD) activity was calculated asthe difference between total SOD and Mn SOD activities. SOD activity wasexpressed as units/mg protein.Catalase (CAT) activity was measured by the method of  Beutler (1982). The methodisbasedontherateofH 2 O 2  degradationbytheactionofCATcontainedin the examined samples followed spectrophotometrically at 230nm in 5mMEDTA, 1M Tris–HCl solution and pH 8.0. The enzyme activity was expressedin   mol H 2 O 2  min/mg protein.The activity of glutathione peroxidase (GSH-Px) was determined using  t  -butylhydroperoxideasasubstratebythemethodof Tamuraetal.(1982)andthe activity was expressed as nmol NADPH oxidized min/mg protein. For determi-nation of glutathione- S  -transferase (GST) activity, 1-chloro-2,4-dinitro benzene(CDNB) was used as a substrate (Habig et al., 1974) and the activity was expressedasnmolGSHusedmin/mgprotein.Glutathionereductase(GR)activ-ity was assayed by the method of  Glatzle et al. (1974) by measuring NADPH oxidation in the presence of oxidized glutathione and the activity was expressedas nmol NADPH oxidized min/mg protein. 2.5. Vitamins C and E analyses Vitamin C (Vit C) concentration was determined spectrophotometrically bydinitrophenyl–hydrazine method at 530nm (Omaye et al., 1979). The method is based on the oxidation of ascorbic acid to dehydroascorbic acid that sponta-neously transforms to diketogulonic acid. In the presence of 2,4-dinitrophenyl-hydrazine, diketogulonic acid forms bis-2,4-dinitrophenyl-hydrazone. Finalcolor development was achieved with 85% sulfuric acid. The concentration of Vit C was expressed in   g/g tissue.Vitamin E was measured by the method of  Desai (1984) based on the reduc- tion of Fe 3+ in Fe 2+ in the presence of tocopherol and production of coloredcomplex with bathophenanthroline. The absorbance of produced complex wasmeasured spectrophotometrically at 535nm. The concentration of Vit E wasexpressed in   g/g tissue. 2.6. Protein concentration The concentration of total protein was determined by the biuret method(Lowry et al., 1951) using bovine serum albumin as standard.   B.I. Ognjanovi´ c et al. / Environmental Toxicology and Pharmacology 22 (2006) 219–224  221 2.7. Statistical analysis The data were expressed as the mean ± S.E.M. and were analyzed by meansof one-way analysis of variance (ANOVA). Statistical evaluation of data wasdone following Student’s  t  -test. A difference was considered significant at  p <0.05. 3. Results The data presented in this work show significant changesin the activity of all examined antioxidant defense enzymes inthe heart during the treatment of rats with Cd (Figs. 1–3). As represented in Fig. 1 exposure to Cd caused an increase activity of CuZn SOD (  p <0.05), while the activity of Mn SOD wasdecreased (  p <0.05). Administration of CoQ 10  and Vit E alone Fig. 1. Activities of CuZn SOD and Mn SOD in the rat hearts of control andexperimentalgroups.Dataareexpressedasmean ± S.E.M. n =8foreachgroups. *  p <0.05 compared to control animals and  #  p <0.05 compared to Cd exposedanimals.Fig.2. ActivitiesofCATandGSH-Pxintheratheartsofcontrolandexperimen-talgroups.Dataareexpressedasmean ± S.E.M. n =8foreachgroups. *  p <0.05compared to control animals and  #  p <0.05 compared to Cd exposed animals.Fig. 3. Activities of GST and GR in the rat hearts of control and experimentalgroups. Data are expressed as mean ± S.E.M.  n =8 for each groups.  *  p <0.05compared to control animals and  #  p <0.05 compared to Cd exposed animals. and/orincombinationwithCddidnotcausesignificantchangesin activity of this enzyme in comparison with control group,while alleviated the harmful effects of Cd.The exposure to Cd resulted in an increase in the activitiesof GSH-Px, GST and GR (  p <0.05), (Figs. 2 and 3), however no significant change in CAT activity was observed (Fig. 2). Treatment with CoQ 10  and Vit E alone and/or in combinationwith Cd caused a decrease in the activities of GSH-Px, GSTand GR (  p <0.05) in comparison with Cd-treated group. Thepresence of the antioxidants minimized the toxic effects of Cdon the affected enzymes.Our results showed that treatment with Cd caused a sig-nificant decrease (  p <0.05) concentrations of non-enzymaticantioxidants (Vitamins C and E) (Fig. 4). The treatment with CoQ 10  andVitEalonesignificantlyincreasedonlyVitEconcen- Fig. 4. Concentrations of Vit C and Vit E in the rat hearts of control andexperimental groups. Data are expressed as mean ± S.E.M.  n =8 for eachgroups. *  p <0.05 compared to control animals and  #  p <0.05 compared to Cdexposed animals.  222  B.I. Ognjanovi´ c et al. / Environmental Toxicology and Pharmacology 22 (2006) 219–224 tration (  p <0.05) in comparison to both control and Cd-treatedrats. While, treatment with CoQ 10  and Vit E alone and/or incombination with Cd caused a increase in the concentrations of Vitamins C and E compared to the group exposed to Cd alone. 4. Discussion 4.1. Cadmium The data presented in this work show significant changesin the activities of all examined antioxidant defense enzyme inheart during the treatment of rats with Cd. The activity of CuZnSOD was increased in heart of rats within 24h of Cd intoxi-cation (Fig. 1). It is known that Cd induces oxidative stress by producing superoxide anion radicals and nitric oxide (Waisbergetal.,2003)anditisreasonabletoexpectanincreasedactivityof CuZn SOD (Kosti´c et al., 1993; Sarkar et al., 1998). In physio-logicalconditions,SODisanimportantintracellularantioxidantwhich catalyses the conversion of the superoxide anion radicalto molecular oxygen and hydrogen peroxide (H 2 O 2 ) and thusprotects against superoxide-induced damage (Mat´es, 2000).Incontrast,theactivityofMnSODinCdtreatedanimalswasdecreased (Fig. 1). Studies of other authors have shown that Cd can inhibit the activity of most enzymes of antioxidant defensesystem (Jamall and Sprowls, 1987; Casalino et al., 2002). This probablyistheconsequenceoftheintracellularaccumulationof ROS with subsequent development of heart injury. We presumethat Cd also enters the mitochondria and inhibits the activitiesof many enzymes by binding to their sulfhydryl groups or byinhibiting the protein synthesis (Stohs et al., 2001).The treatment with Cd significantly increased the activitiesof GSH-Px, GST and GR in the heart (Figs. 2 and 3). However, no significant change in CAT activity was observed (Fig. 2). Exposure of rodents to Cd has been reported to increase thelevels of MT and GSH and in some studies it has increased theactivitiesofantioxidantenzymesSOD,GSH-PxandGRinvari-oustissues(Casalinoetal.,1997;O’BrienandSalasinski,1998;Ognjanovi´cetal.,2003).TheGSHredoxcycleisamajorsourceof protection against low levels of oxidant stress, whereas CATbecomes more significant in protecting against severe oxidantstress (Mat´es, 2000). Cd-induced increase in GSH-Px activitymay be explained by his influence on H 2 O 2  as substrate whichis formed in the process of the dismutation of superoxide anionradicals (Shaikh et al., 1999). In addition, the GSH redox cycle, which includes GSH, GSH-Px and GR, plays an important rolein the detoxification of ROS that are generated by Cd, so asto protect cells from the potential toxicity and carcinogenesis(Griffith, 1999; Mat´es, 2000).The cysteine thiol groups of MT may be involved in itsantioxidant properties in protecting tissues from hydroxyl radi-cal attack. MT, increased by a low doses of Cd (0.2 and 0.4mgCd/kg), played an important role in protecting testis and liveragainst Cd toxicity (Xu et al., 2005).The increase in the activity of GST in the heart (Fig. 3) is in agreement with the finding of our previous investigations whichshowedthatexposuretoCdcausedanincreasedactivityofGSTinliverandplasmaofrats(Ognjanovi´cetal.,1995,2003).Otherauthors showed that Cd exposure increased the activity of thisenzyme in different tissues. Indeed an increased hepatic GSTactivity in rat (Casalino et al., 2004) and guinea pig (Iscan et al., 1994) has been observed. The GST enzyme has an importantrole in detoxification of xenobiotics, drugs and carcinogens andthus protects the cells against redox cycling and oxidative stress(Mat´es, 2000; Casalino et al., 2004).Results showed that treatment with Cd caused a significantdecrease of the concentration of non-enzymatic antioxidants(Vitamins C and E) in the heart (Fig. 4). Our previous investiga- tions showed that chronic treatment with Cd induced a decreaseof Vit C concentration in the liver (Ognjanovi´c et al., 1995) andkidneys (ˇStajn et al., 1997) of young and adult rats, while Cdincreased the concentration of Vit E in rat liver (Ognjanovi´c etal., 1995), kidneys (ˇStajn et al., 1997) and plasma (Kosti ´c etal., 1993; Ognjanovi´c et al., 2003). It is known that increasedaccumulation of Cd in the liver induces lipid peroxidation andincreases the production of malondialdehyde (MDA) (Xu et al.,2005),whichconsequentlyinhibitstheenzyme l -gulonolactoneoxidase (Shukla and Chandra, 1989, Gupta and Kar, 1998) nec- essary for the synthesis of Vit C which is a potent scavengerof free oxygen radicals and its deficiency results in intracellularoxidative damage in the guinea pig (Nagyova et al., 1994). Vit E is a major free radical chain-breaking antioxidant and alsocan interfere with the initiation and progression of Cd-inducedoxidative damage. Vit E is the primary liposoluble antioxidantwhich may have an important role in scavenging free oxygenradicals and in stabilizing the cell membranes, thus maintainingits permeability (Beyer, 1994). 4.2. Coenzyme CoQ 10  and Vitamin E  A number of nutrients have been shown to interact with Cdand alter its cellular effects. Several protective agents, includingGSH and MT, as well as selenium, ascorbic acid, beta-caroteneandVitEplayanimportantroleindetoxificationofendogenousand exogenous compounds (Chan and Cherian, 1992; Chen andTappel, 1995; Ognjanovi´c et al., 2003).A large number of reports (Stohs and Bagchi, 1995; Sarkaret al., 1998) indicate that one of the mechanisms underly-ing cadmium-induced cellular toxicity is free radical-mediateddamage. As a consequence of ameliorated oxidative stress andROS the activities of heart enzymes (Figs. 1–3) were partially restored. Thus, the present results indicate that adequate antiox-idant status may protected rats from heart damage after Cdtreatment.TheantioxidantenzymessuchasSOD,CAT,GSH-Pxand GST dismutate the free radicals and reduce H 2 O 2  toxicityby its decomposition or by reduction of peroxides by GSH viaGSH-Px. Shaikh et al. (1999) concluded that oxidative stressappears to play a major role in chronic Cd-induced hepatic andrenal toxicity since inhibition of components of the antioxidantdefensesystemacceleratedandadministrationofVitEprotectedagainst Cd toxicity. Also, carotenoids can function directly asantioxidants by reacting with active oxygen species (Chen andTappel, 1995).Treated with CoQ 10  and Vit E alone and/or in combinationwith Cd caused a decrease in the activity of CuZn SOD, while   B.I. Ognjanovi´ c et al. / Environmental Toxicology and Pharmacology 22 (2006) 219–224  223 the activity of Mn SOD was increased (Fig. 1) in comparison with Cd-treated group. It is demonstrated that SOD exhibitsa novel function as a superoxide semiquinone oxidoreductase(Cadenas et al., 1988). In this reaction, SOD reacts with hidro- quinones and together with enzyme DT-diaphorase (NAD(P)H:quinine acceptor) oxidoreductase inhibits auto-oxidation of hydroquinones. This reaction is important for maintenance of semiquinonesonitsreduced,biologicallyactiveform.IncreasedactivityofMnSODisprobablyresultofincreasedincorporationofCoQ 10  inheartmitochondrialrespiratorychainandincreasedproduction of superoxide anion radicals in mitochondria (Lasset al., 1999; Shi et al., 1999). Treatment of rats with CoQ 10  andVit E diminished the toxic effect of Cd on CuZn SOD and MnSOD activities. It is known that CoQ 10  induces an elevation of Vit E concentration in tissues of rats and it is known, that therate of superoxide anion radicals elimination is directly relatedto the Vit E concentration indicating the role of Vit E in thiselimination of radicals (Shi et al., 1999).Administration of CoQ 10  and Vit E alone and/or in com-bination with Cd did not cause any significant change in theactivitiesofGSH-Px,GSTandGR(Figs.2and3),incomparison with control group, while alleviated the harmful effects of Cd.However, no significant change in CAT activity was observed(Fig. 2). The presence of the antioxidants minimized the toxic effectsofCdontheaffectedenzymes.CoQ 10  byquenchingROScan be indirectly involved in the regulation of gene expressionand in modulation the activities of most enzyme. On the otherhand, dietary CoQ 10  has been reported to have a sparing effecton alpha-tocopherol, which increases in mitochondria of heart,skeletalmuscleandkidney(Lassetal.,1999).Ourearlierexperi- ments(Pavlovi´cetal.,2001)alsoshowthatCoQ 10 ,byelevatingGSH-Px activity can protect the cells against Cd peroxidativedamage.TreatmentwithCoQ 10  andVitEaloneand/orincombinationreversed Cd-induced alterations in Vit C and Vit E concentra-tions (Fig. 4). On the other hand, results showed that only Vit E concentration is elevated by the combined treatment of CoQ 10 and Vit E as compared to controls (Fig. 4). However, treatment with CoQ 10  and Vit E alone and/or in combination with Cdcaused an increase in the concentrations of Vitamins C and Ecompared to the group exposed to Cd alone.The Cd-induced depletion of water-soluble and lipid-solubleantioxidants has led to the increased susceptibility of the tis-sues to free radical damage. Increased concentration of Vit Cin the heart of rats treated with CoQ 10  and Vit E alone or incombination is in accordance with increased concentration of Vit E because they act sinergically as antioxidants and eachcan exert sparing effect in the absence of the other (Shukla andChandra, 1989; Beyer, 1994; Ibrahim et al., 2000). It is wellknown that CoQ 10  and its NADPH-dependent reductase stabi-lized the extracellular ascorbate in the organism (Beyer, 1994).Ontheotherhand,VitEradicals(  -tocopheroxylradical)wouldbe regenerated by reduced form of CoQ 10  (CoQ 10 H 2 ) and thiscould be the explanation for increased concentration of Vit Ein heart of rats treated with CoQ 10  (Chen and Tappel, 1995;Ibrahim et al., 2000). The potential of CoQ 10  to regenerate VitE via electron transport from Vit E radicals serves to preserveother cellular reductants, such as Vit C and GSH, which other-wise could provide only limited maintenance of reduced Vit Eduring oxidative stress. CoQ 10  is directly reduced by NADH-cytochrome  b 5  reductase, ferredoxin reductase and glutathionereductase, it maintains both Vit C and Vit E in their reducedstate. These facts suggest that CoQ 10  and system involved inits oxidation/reduction might behave as regulators of cellularredox status and antioxidant capacity and should be consideredas a part of the protective cellular response to oxidative injuries(Beyer, 1994; Ernster and Dallner, 1995; Shi et al., 1999).TheseresultsareinagreementwiththoseobtainedbySuginoet al. (1989) who found that exogenously administered CoQ 10 (oxidized) accumulated in the liver and showed a maximalplateau between 8 and 16h after injection when 82% of CoQ 10 was converted to the reduced form. Tocopherol administeredalso showed an 84-fold accumulation in the liver 8h after injec-tion (Sugino et al., 1989). We heve also shown that Cd-induced oxidative alterations can be prevented by several antioxidantssuch as selenium (Jamall and Sprowls, 1987; Ognjanovi´c et al.,1995; ˇStajn et al., 1997; ˇZiki´c et al., 1998),  N  -acetylcysteine(Shaikh et al., 1999; Tandon et al., 2003) and Vit C (Nagyova et al., 1994; Gupta and Kar, 1998). Peters et al. (1995) observed that Vit C and GSH were effective in reducing the toxic effectsof low concentrations of Cd on two-cell stage mouse embryos.In conclusion, our study suggests that the prooxidative effectof Cd is responsible for alterations in prooxidant–antioxidantbalance in the heart. The results of our work suggest that CoQ 10 acts as a potent antioxidant in combination with Vit E in protec-tion of rat heart against oxidative stress induced by Cd. Theseresults support the assumption that administered CoQ 10  andVit E alone and/or in combination functions cooperatively withendogenous antioxidants in reducing the harmful effects of Cd. Acknowledgement This work was funded by the Ministry for Science and Envi-ronmentalProtectionofRepublicofSerbia,GrantNo.143035B. References Andr´ee, P., Dallner, G., Ernster, L., 1998. Ubiquinol: an endogenous lipid-soluble antioxidant in animal tissues. In: ˝ Ozben, T. (Ed.), Free Radicals,Oxidative Stress and Antioxidants. Plenum Press, New York, pp. 293–314.Andersen, O., 1999. Principles and recent developments in chelation treatmentof metal intoxication. Chem. Rev. 99, 2683–2710.Beutler, E., 1982. Catalase. In: Beutler, E. (Ed.), Red Cell Metabolism, AManual of Biochemical Methods. Grune and Stratton, New York, pp.105–106.Beyer, R.E., 1994. The role of ascorbate in antioxidant protection of biomolecules: interaction with Vitamin E and coenzyme Q. J. Bioenerg.Biomemb. 26, 349–358.Cadenas, E., Mira, D., Brunmark, A., Lind, C., Segura-Anguilar, J., Ernster,L., 1988. Effect of superoxide dismutase on the autooxidation of varioushydroquinones-a possible role of superoxide dismutase as a superoxide:semiquinone oxidoreductase. Free Radical Biol. Med. 5, 71–79.Casalino, E., Sblano, C., Landriscina, C., 1997. Enzyme activity alterationby cadmium administration to rats: the possibility of iron involvement.Arch. Biochem. Biophys. 346, 171–179.Casalino, E., Calzaretti, G., Sblano, C., Landriscina, C., 2002. Molecularinhibitory mechanisms of antioxidant enzymes in rat liver and kidney bycadmium. Toxicology 179, 37–50.
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