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Figure 10: Chemical struclurc nf tcrt-butyl bydropero1ide (t-BHP)

As o prooxidunl. lhc effects of t-131 IP on cell mclllbolissn hove been ,veil documented (Nicotera cl al., 1988). T\\·o mcchnni:.ms hove bc:1::n proposed for lhe actions or 1-0l lP: depletion of cellular stores or GSll und o,cidotion of functionnll) importnnt Sil

groups on mitochondrial cn7yn1c� (Mosoki ^cl al. 1989) tind chnng� ^HI mi1oc:J1ondnlll membrane 1n1cg.rity induced by pcroxidotion of mcn1bmnc lipids (Rubin ond Fnrl>cr, 1984}.

ac.,idc:s thc:sc, t-81 u> hns olso been Involved in the oxidative modilicntion <>f ,ron-sulfur

clusters in vnriou.� c07.Ymc complexes (Nc,,comb .:I al .. 1996; Gcnovu et al. 2001). It hiu been sUS(tc:!Slcd thnt t-DIU' is dccompoi;cd in the prcscnee offc'• 10 yield n mdicnl

1-DIIP-0-0· (Fis. 11) (Newcomb et al., 19%).

re'' Du'OOII • :> ^{fe 1 -0-0-0u' ( la)}

re ¹ ' ·0-o. Du' :> ^{Fe· -+} •• ·o-O,Du' (It,}

f c: ^l • ^t llu'-0011 ,. II'• > _{r ,.} ^{Cl •} uu' c>' ^T I hll 12) nu•-o· ^I 11<)-C),llu' < ^{I nu',Cll I} • 1311'•(),( )' (3)

C :>

1111 ^{1 -()} <'ll1- UNIVERSITY _I ""> 1111 ¹ ·011 ^I :c ^{II ,-} ₍₄₎

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As a prooxidant. t-BHP has bcc:n used in various studies as a model of oxidative llrcss (Drahota cl al., 200S). Its many effects on cell metabolism such as chanaes ⁱⁿ

calcium homeostasis (Nicotcna cl al., 1988; Elliot and Doan, 1993; Elliot cl al., 1995) and

increase of lipid pcroxidation or decrease of mitochondrial membrane potential (KmonU!kova cl al.. 2001) ha, been established. Likewise. the effect of I-BHP on hypertension and nging hos been documented (Garcia-Cohen cl al., 2000). t-81-IP is ^of

modemle ncutc toxicity vio nll routes of exposure:. Ingestion may rcsull in seven:

discomfort. pronounced gnstroin1es1innl irritation, nnd intc:mnl bleeding. while exposure 10 vopor or aerosol may cau.'IC marked irrilnlion of the eyes nnd respiratory IJ'act. Skin or eye contoct leads lo irritation, redness, nnd chemical burns. Cieslinski cl al. ( 1987) n:portcd that

t-BIIP dccn:nscd rabbit n:nal proximal tubular glutathionc Dnd potassium contents and increased lipid pcroxidation. In addition. they demonst.nltcd thnt tubules with decreased

glutathione concent.n1tions \\-ere mon: sensitive thDn normal cells to t-BHP (Schnellmann.

1988). Zou et al. (2001) in their study sho"-cd that incubation of RDC with t-BIIP for 10 min resulted in the formation of TBARS, oxidation of haemoglobin and degradation and oggrcption of membrane proteins Likewise in the erythrocyte, t-01-IP has been rcponcd to increase membrnnc permeability to er . K' ond low molecular weight supn, u well u

causinai nltcrutions in cell dcformability (Dwight and Hendry, 1996).

Numerous invc.-1tigoto13 have used crythruc:yte as model systems for SIUd)i ^"I biomcmbrnnc oxidative damage (Niki et al., 1988; Mobile et al., 2001). In many oft�•

studies, fn:c nidicnl initiators weh ^iu tcrt butyl hydroJ!CRlxidc (t·BIIP), 2. 2-azo bis (2-amidinopropane) dihydrochlondc (AAPII) and hydroam peroxide (HzC>l) have t,.,. ¹¹ uxd 10 llfflCT&le fn:c nidicals in the aqucou� phase that can attack lhc CT}1hroc)u 11.c:anb.w .ad prop11gatc lipid pcmiudauon, leading to hcmoly,as (N1li rt al ,. 19111; �tabile ct al. _2001).

F.t)'1hmc)10 arc 1ntnns1CAII) prone to o,.acbu,·c •� giVlna nsc to lrpid rm-•We•"ffl and llltunatcly hcmnlr-b Jue to their high content of polyunselWlltN hi,ids. lhcir rich o.,)sm supply and the prtKnec of transition metal� (fmclra rt al� 1999, Ji:.uuthip .- Ill. 200n

Racu� oxy1tcn spccics (ROS) generated In lhc ^aQIK'._ or llpd r,haw ta M!e-:\

ft)'lhroc)1e manbnu,a and Induce lhc o,udatlon of Upds end l'R*"- lnAJl'NII

da,rupclom In the mcrntw-- and thm hc:11.oly,n (�IIU ,, al 19'7 il1 -1 l1l lllf.ltK Fthmoo and uen 2002) Rmctlw ^OXYJffl ,r«la lw\-e tlQ l,c,c,n -.,lie ltJ ta 1 "I' ff)1hn:,c,tn n ratlffllt ...-Ith �the.l11vmla. •�at ^{ttll s,} v-. ••• ^•,�o,n

-d .t)d.uflW I UNIVERSITY drtkk"ncy end ndln ha,,,.sc.ti1 ... ^{(II ..}

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2.7 LlPID PEROXIDATION

Lipid pcroxidolion has been defined by Toppcl ( 1979) as the oxidative dctcriorouon of polyunsaturated lipids (polyunsaturated forty acids, PUFA) thn1 is lipids that contain more Lhun l\vo carbon-cnrbon double covalent bonds [ :::: C - C. g . ^{Since the}

membranes surrounding cell and cell orgnncllcs contain large nmount of pol _yu =turoled folly oc1d side chains, biolog1col membranes have been a moJor o.nd nolllble lnrget of lipid pcro,idouon

The oxidative dclcriornlion or modilicolion of hp1ds is inilio1ed by reactive oxygen species (ROS) es�-ciolly hydroxyl rodicol (01 I), olkoxy rod1cols (RO), and peroxy radicals (llOO ^{° )} , (lurrcns ond Bovcns, 1980; Gnrdencr, 1989, Pinchuk et al., 1998. Nynka tmd Kohen. 2002, Valko ,:t ul, 2006). These reacuve �pcc,cs n=act ,,·ith membrane lipid�, prolc1ns nnd nucleic ocids as inillolor nnd propagator of trun,fcr of electrons bringins about ox,douon of subs1r111cs. The presence or double bond 1Mljnccn1 10 o mclhylcnc group mru..es the methylene C 11 bonds of polyunsoturotcd folly ocid (T'Ur A) ,,'COJ..er and the hydrogen becomes prone 10 nbstmction.

The ROS uuocl. on the cell membmncs consequently lcods to elulni;cs in membrane nuid11y. permeability and cellular me14bolie functions. Other properties such as ion

tnuuport, enzyme oeU\'lly, protein cross-linking. ond protein iynthcsis ^w,: al50 ltf'O!SSI) olTccted leading ultimately 10 ON'\ damngc: and cell death, (llalli-�-cll IUld Guucridsc, 1990), The proc:cs, of lipid pcro:ud:ltion in,oh,c., both initiAtion and pmpapuon SUlgC5.

The iniliJtion sllli;e 1n,ol\cs the attuck of ROS on methylene ( -c11, - ) goup lha ^c b) abstracting a hydroiicn atom Dnd lc:a\.ins behind an unpaired electron on the ca,bon c-·c1t J

-). 1nc Cllfbon rudiCAI form<-J thu, tcnJ.s to be 1111biliTcd h)' • molecular �I to fonn a conjuptc:J dlc:nc. 11,is can come: 1n10 contoct "ith1n the mc,ubcu..c "lib nnodicr c:onJui::,-iled dienc thacb) cro��linl1ng the folly ocid molcculo. On the other t.:m.1,

C:Ol1JUl!JIIN dic:nc, '110$1 lilcly under ncrublc conJitions combine \\lth <>J to r,n-.: a rau",1

mdla.1, R<X ^f (or RC>J) of\m UID\\11 ^M �m.._y ffllliC111, (I tr,. 10)

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Fatly acid ...,;th double bonds

-l molecular rcanuangc:mcnt

- Congugnted dicne \\ith UV

- - obsorb:mee ot 234nm

• 1� C>-<ygm upuikc

Pa-o"Y rodienl:obstroclS I r from onolh�-r fatty ncid causing on

- ^- nu1oeo1nlyic chllin rc:ietion

g ^{• 1r}

- - Lipid h) dropcmxidc

I

l'h:urc 12: Mcchnnum or llphl l'cro,LIJ11tion b) ROS f'n1m: llallhvcll and Gullt'ridgc, 1989

Tl1c pcrnxy rntllcnl-9 1h11:1 formed ^lll'C capnble of ob,uucling hydrogen from nnothcr lipiJ molecule. �peclolly on udjsccnt foll)' ochl �ldc-chnin

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lnl• I� the propc1g:,tiun �L11ic whereby the c11rbun roJicu1 funnc,J m'4;ts \\ilh l)l 111 1cin11 1U1othcr ro:"'"Y nadiclil tllld "'' 1hr ch�ln �11ction UNIVERSITY ur 111'111 rcn,,id.uh•n ,-.,nun"'-,. rlw

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peroxy radical ^n:acts with ^the hydrogen alOm abstracted ^to give a Upid hydropcroxidc ^(lipid

pe co.Jde) which can give rise to other products such u cyclic peroxide. cyclic endo _pe roxide and maloodialdehyde.

Various methods and techniques have been employed in the measurement of lipid

pe roxidation, among which arc mc:asumneot of conjugated dicnc. the thiobmbituric acid (TBA) test, measurement of peroxides and maasurc:mcnl ofaldchydcs.

Lipid pcroxidation is nol peculiar to biological membranes only, other biological tiswcs and cellular components an: equally prone to lipid pcroxidalion (Valko�, al., 2006).

Likewise, oxygen-dependent detcrior:1tion leading lo l"IIDcidity has been a major problem in the storage of fDlS and oils. Also painlS, plastics. lacquers, rubber and cooking oils can undergo oxidative damage.

2.8 ANTIOXIDANTS

Antioxidllnl as described by Halli\\1:II and Gutteridge ( 1999) is any subst1111Ce that.

when prcscnl 111 low conccntnuions with those of an oxidisable substnatc, significantly delays or pn:vcnlS oxidation of1ha1 substnatc. The term oxidi,ablc subsbUte includes every type or molecule round In v/1·0. These subs111nccs which arc also kno\\11 as �llular dcrcnce qmts M\e both enzymatic and non eDZyIN1tic dercnce mechanisms against damqc by fn:e.nidicals or non rodical ROS. Q,cidation is n chemical miction that bUnSfcrs electrons rmm a substance 10 an oxidizing agcnL Oxida1ion reactions can produce fn:e radicals,

\\·hich could !illlrt chain mactions tbal will ultimately damage cells. Antioxidants piny n good role in 1crmi11.11ting these chllin reoctions by rcrnovin, tiff radical 1n1e1111edlatcs, and

inhibiting other oxidation reactions by bcina oxidiz.ed themscl\u. As• result. antioxidant1 arc oncn reduc:ina ngcnL• !lUCh as thiol, or polyphcnols.

The a,uioxidnnt c.npacity or any cc.mipowid I, based on its 5UUC1unal fcan-s, such a the

number and po,l1111n or double bonch, hydroxyl-pups and modifications such u I�

to supr moic:tiN (Ko1lk0Wlki ^tl al. 2003)

Mode or anlo• or Aalloaldaac,

� an: four ruuta

1. Chain bmlklna racuons • alJlha·klalf'hmll ""hlch acta In llrld flll!IW 1o trap ...tab.

1, Reduclna the coocentndon UNIVERSITY of l'ftlCllve oll)'lffl ._,«1n 1lu111duune

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Scavenging initiating radicals - supcroxidc dismutase which acts in aqueous phase ^to

tl'8p supcroxidc radicals.

Chelating the transition mclDJ calDJysts: this group of compounds functions by sequestration of transition melDJs lb.at are \\.-ell-established pro-oxidants. For example.

transferrin, loclofcrrin, and ferritin function ^lO keep iron induced oxidant sacss in check lllld ccruloplasmin and albumin ns copper scqucstrunts

2.8.1. Enzymatic: antiosidanls I. Supc:roxidc: dlsmutallr

Supcroxidc dismuto.sc (SOD). is a melllJloenzyme that calDJyscs the dismutnlion or disproportionation of supcroxide ions.

----.. .ioHhO, • 0:

SOD

Two forms of supcrocidc d1smuto.sc c:,ist; a C)tosolic copperand zinccontaining enT)me -CuZnSOD ond a mitochondrial mongnncsc-contain,ng enzyme MnSOD. The presence of lhc:sc c:n.cym�� an hi&h concc:ntrntioru. in 1111 tis.sucs together \\ith their high atolytic efficiency (rutc: c:ons1ru11 2 x 10· ⁰ litre: mor's 1) pro\;dcs a high degree of cellula.r protection 11gn1nst supcroxide union rudicnl under normal condition.

2. Catala,c

C.Otnliuc, o tc:tnuncric: hemoprotcin i, c:mplo}c:d in the dcto,ulication of hydrogm

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