Biological Functions and Metabolic Fate

8/13/2019 Biological Functions and Metabolic Fate

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R e v i e wJou rnalof I I II IIIIIIIIIIi omed i ca lSc i ence J B i o m e d S c i 2 0 0 4 ; 1 1 :2 9 5 - 3 0 2D O I : 1 0 . 1 1 5 9 / 0 0 0 0 7 7 0 9 7

Rece ived: November 19 2003Accepted : November 19 2003

i o lo g i c a l F u n c t i o n s a n d M e t a b o l i c F a t eo f V i t a m i n E R e v i s i te dC h i n g K u a n g C h o wG r a d u a t e C e n t e r f o r N u t r i t i o n S c i e n c e s a n d K e n t u c k y A g r ic u l t u r a l E x p e r i m e n t S t a t io n U n i v e r s i t y o f K e n t u c k yL e x i n g t o n K y . U S A

K e y W o r d sV i t a m i n E B io log ica l funct ion v i tam in E Me tabo l ism/ fa te v i t amin E

b s t r a c tIn fo rmat ion accumula ted la te ly has con f i rmed the essen-t ia l i t y o f v i tam in E fo r hum ans and prov ided a be t te runders tand ing o f i t s b io log ica l funct ion and metabo l icfa te . The d iscovery o f a - tocophero l t ransfe r p ro te inwh ich preferen t ia l ly b inds to RRR-a-tocopherol not onlyprov ides conc lus ive ev idence o f the essent ia l i t y o f v i ta -min E fo r hum ans bu t a lso sheds l igh t on the super io r i t yof RRR-a-tocopherol b io lo gica l ly over other isomers. Thepresence o f tocophero l regenera t ion sys tems and m u l t i -p le in te rdepende nt an t iox idan t system s is la rge ly re -spons ib le fo r the lack o f a w idespread de f ic iency inhumans and the d i f f icu l ty to dep le te v i tamin E in theadu l t . The bu lk o f excess tocophero ls consumed is ex-cre ted to feces unchanged o r to u r ine w i th the s ide chainshor tened bu t the chroman r ing in tact . The ab i l i t y o fd ie ta ry v i t amin E t o m ed ia te m i t ochond r ia l supe rox idegenera t ion a f fo rds a poss ib le m ode o f ac t ion o f v i tam in Eat the t issue levels. By decreas ing the genera t ion and /o rthe leve ls o f react ive oxygen /n i t rogen spec ies d ie ta ry

vi tamin E no t on ly p ro tects aga inst ox ida t ive damagebut a lso modu la tes the express ion and /or act iva t ion o fredox-sens i t ive b io log ica l response mo d i f ie rs tha t regu-late important cel lu lar events.

Copy right 2 004 National ScienceCoun ci l ROC and S. Karger AG Basel

I n t r o d u c t i o nV i t a m i n E i s t h e t e r m r e f e r r i n g t o a ll t o c o l a n d t o c o t r i e -

n o l d e r i v a t i v e s q u a l i t a t i v e l y e x h i b i t i n g t h e b i o l o g i c a l a c -t i v i ty o f R R R - a - t o c o p h e r o l . T h e t e r m ' t o c o p h e r o ls ' i s t h eg e n e r i c d e s c r i p t i o n f o r a l l m o n o - , d i - a n d t r i m e t h y l t o c o l sa n d t o c o t r i e n o l s a n d i s n o t s y n o n y m o u s w i t h ' v i t a m i n E ' .T h e r e a r e f o u r t o c o p h e r o l s ( t o c o s ) a n d f o u r t o c o t r i e n o l st h a t o c c u r n a t u r a l ly , d i f f e r in g i n th e n u m b e r a n d p o s i t i o no f m e t h y l g r o u p s o n t h e c h r o m a n r in g . A l l e i g h t n a t u r a l lyo c c u r r i n g t o c o p h e r o l c o m p o u n d s i s o l a t e d f r o m p l a n ts o u r c e s h a v e a 6 - c h r o m a n o l r i n g ( h e a d ) a n d a p h y t y l s i d ec h a i n ( t a i l ) [4 , t 5 , 4 0 ] . T o c o t r i e n o l s h a v e a s i m i l a r s t r u c -t u r e t o t h a t o f t h e i r c o r r e s p o n d i n g t o c o p h e r o l s , e x c e p tt h a t t h e s i d e c h a i n c o n t a i n s t h r e e d o u b l e b o n d s a t t h e 3 ' ,7 , a n d 1 1 p o s i t i o n s .

I n a d d i t i o n t o t h e n a t u r a l l y o c c u r r i n g i s o m e r s , s e v e r a lt y p e s o f s y n t h e ti c v i t a m i n E , e i t h e r i n f r e e o r e s t e r fo r m s ,

K A R G E RF a x + 4 t 6 1 3 06 1 2 3 4E-Mail karger@karger, chunvw.k a r g c r . c o m

2 0 0 4 Nat i o n a t Sc i en ce C o u n ci l , R OCS. Karg e r AG, B ase l1 0 2 1 -7 7 7 0 / 0 4 / 0 1 1 3 -0 2 9 5 5 2 1 .0 0 / 0Accessible o nl ine a tw ~ v . k a r g e r . c o m / j b s

D r . C h i n g K u a n g C h o wGrad u at e C en t er f o r Nu t r i t i o n a l Sc i en ces, U n i v er s i t y o f Ken t u ck y3 0 8 Fu n l d ao u d er B u i l d in gLexington, KY 40506-005 4 USA)TeI . +1 8 5 9 2 5 7 7 7 8 3 , E-Mai l ck ch o w@ u k y .ed u


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a r e a v a i l a b l e c o m m e r c i a l l y . A s t h e e s t e r f o r m , s u c h a s a -t o c o p h e r y l a c e t a t e , i s l e s s s u s c e p t i b l e t o o x i d a t i o n , i t i sm o r e s u i t a b l e f o r f o o d a n d p h a r m a c e u t i c a l a p p l i c a t i o n st h a n t h e f r ee f o r m . T h e n a t u r a l ly o c c u r r i n g a - to c o p h e r o l ,f o r m e r l y k n o w n a s d - a - t o c o p h e r o l , is n o w d e s i g n a t e d a sR R R - a - t o c o p h e r o l . T h e s y n t h e t i c a - t o c o p h e r o l , w h i c hc o n s i s ts o f ei g h t s t e re o i s o m e r s [ 2 D , 4 ' D , 8 ' D ( R R R ) ,2 L , 4 ' D , 8 ' D ( S R R ) , 2 D , 4 ' D , 8 ' L ( R R S ) , 2 L , 4 'D ' 8 ~ L (S R S ) ,2 D , 4 ' L , 8 D ( R S R ) , 2 L , 4 L , 8 ' D ( S S R ) , 2 D , 4 L , 8 ' L ( R S S ) ,a n d 2 L , 4 ' L , 8 ' L ( SS S )] [ 4 0 ] , p r e v i o u s l y k n o w n a s d /- a - to -c o p h e r o l o r 2DL,4 DL,8 DL-tocopherol, i s n o w c a l l e d a l l -r a c - a - t o c o p h e r o l .

V i t a m i n E w a s d i s c o v e r e d o v e r 8 0 y e a r s ag o [ 2 4] . H o w -e v e r , d u e t o t h e l a c k o f a d e f i n i t e c l in i c a l s y n d r o m e a t tr i b -u t a b l e t o i t s d e fi c i e n c y , t h e n e e d o r u s e o f v i t a m i n E f o rh u m a n s h a d b e e n q u e s t i o n e d . L a t e ly , w i t h t h e r e c o g n i t io no f a r o l e o f f r e e ra d i c a l s i n t h e p a t h o g e n e s i s o f d e g e n e r a -t i v e d i s e as e s, a n d p o s s i b l e p r e v e n t i o n o f t h e s e d i s e a s es b ya n t i o x i d a n t s , t h e r e h a s b e e n a r e n e w e d a n d e x p a n d e di n te r es t i n v i t a m i n E . T h e l ar ge a m o u n t o f i n f o r m a t i o na c c u m u l a t e d t o d a t e h a s c o n f i r m e d t h e e s s e n t i a l i t y o fv i t a m i n E t b r h u m a n s a n d p r o v i d e d a b e t t er u n d e r s t a n d -i n g o f i ts r o l e i n c e l l u l a r f u n c t i o n s . T h i s a r t ic l e f o c u s e s o nt h e b i o l o g ic a l f u n c t i o n s a n d m e t a b o l i c f a te o f v i t a m i n Ew i t h s p e c i f i c r e f e r e n c e t o s e v e r a l l o n g - p u z z l i n g q u e s t i o n so f it s r o l e in h u m a n n u t r i t i o n .

I s V i t a m i n E I n d e e d E s s e n t ia l f o r H u m a n s

p a t i e n t s w i t h a v a r i e t y o f fa t m a l a b s o r p t i o n c o n d i t i o n s ,s u c h a s a b e t a l i p o p r o t e i n e m i a , c h r o n i c c h o l e s t a t ic h e p a t o -b i l i a D d i s o r d e r , a n d c y s t i c f i b ro s i s .

C o n c l u s i v e e v i d e n c e o f th e e s s e n t i a li t y o f v i t a m i n E f o rh u m a n s w a s o b t a i n e d f r o m s t u d i e s o f p a t i e n t s w i t h f a m i l-i a r i s o la t e d v i t a m i n E d e f i c ie n c y o r a t o x i a w i t h i s o la t e dv i t a m i n E d e f i c i e n c y i n t h e 1 9 9 0 s . T h e s e p a t i e n ts , w h oh a v e n o m a l a b s o r p t i o n s y n d r o m e , h a v e n e u r o lo g i c al d y s-f u n c t i o n s a n d e x t r e m e l y t o w s e r u m v i t a m i n E l e v e ls [4 3 ,7 3 ] . S u b s e q u e n t s t u d i e s d e m o n s t r a t e d t h a t t h e v e r y l o wv i t a m i n E s t a tu s o f t h e s e p a t i e n t s i s a t tr i b u t a b l e t o t h e i ra b s e n c e o f a - to c o p h e r o l t r a n s f e r p r o t e i n ( a - T T P ) . a - T T P ,w h i c h i s a c y t o s o li c p r o t e i n w i t h h i g h a f f i n it y t o R R R -a - t o c o p h e r o l , i s r e q u i r e d f o r t h e s e c r e t io n o f t o c o p h e r o li n t o l i p o p r o t e i n s a n d f a c i l i t a t e s i t s r e t u r n t o t h e l i v e r , a -T T P i s t h e m a j o r i n t r a c e l lu l a r t r a n s p o r t p r o t e i n f o r v i ta -m i n E w h i c h m e d i a t e s a - t o c o p h e r o l s e c r e t i o n i n t o t h ep l a s m a v i a a n o n - G o l g i - d e p e n d e n t p a t h w a y , w h i le o t h e rb i n d i n g p r o t e i n s s e e m t o p l a y a l e ss i m p o r t a n t r o l e [ 38 ].T h e h u m a n a - T T P g e n e i s l o c a t e d a t c h r o m o s o m e 8 q 1 3[ 1 , a n d m u t a t i o n s o f t h e g e n e i m p a i r s e c r e t i o n o f t o c o p h -e r o l i n t o h e p a t i c l i p o p r o t e i n s . S t u d i e s o f t h e g e n e s t ru c -t u r e a n d m u t a t i o n s o f a - T T P o f p a t i e n t s w i t h f a m i l i a l i so -l a t e d v i t a m i n E d e f i c i e n c y c o n f i r m a c r i t i c a l ro l e o f c c -T T Pi n m a i n t a i n i n g a n a p p r o p r i a t e v i t a m i n E s t a te [ 1 , 3 4 , 5 3 ,7 3 ]. A s h i g h d o s e s o f v i t a m i n E c a n p r e v e n t o r m i t i g a t et h e n e u r o l o g i c a l c o u r s e o f t h e p a t i e n t s , a d i r e c t t r a n s f e r o fs o m e t o c o p h e r o l f r o m c h y l o m i c r o n s t o o t h e r c i r c u la t i n gl i p o p r o t e i n s m a y o c c u r [ 28 ].

V i t a m i n E w a s f i r s t r e c o g n i z e d a s a l i p i d - s o l u b l e s u b -s t a n c e n e c e s s a ry f o r t h e p r e v e n t i o n o f fe t a l d e a t h a n dr e s o r p t i o n i n r a t s t h a t h a d b e e n f e d a r a n c i d l a r d d i e t [ 2 4] .A l s o , a n u m b e r o f s p e c i e s - d e p e n d e n t d e f i c i e n c y s y m p -t o m s o f v i t a m i n E , s u c h a s l iv e r n e c r o s is i n r a t s a n d p i g s,e r y t h r o c y t e h e m o l y s i s i n r a ts a n d c h i c k e n , a n d w h i t e m u s -c l e d i s e a s e i n c a l v e s , s h e e p , m i c e , a n d m i n k , w e r e r e -p o r t e d d e c a d e s a g o [ 59 ]. H o w e v e r , t h e n e e d o f v i t a m i n Ef o r h u m a n s w a s q u e s t i o n e d d u e t o t h e l a ck o f a d e f i n i t ec l i n i c a l s y n d r o m e a t t r i b u t a b l e t o i t s d e f i c i e n c y , t h e a b -s e n c e o f a w i d e s p r e a d d e f i c ie n c y i n h u m a n s , a n d t h e d i f fi -c u l t y o f i n d u c i n g a d e f i c i e n c y i n h e a l t h y a d u l t s [ 32 ].

I n th e l a t e 1 9 6 0 s, th e n e e d o f v i t a m i n E f o r h u m a n sw a s r e c o g n i z e d i n c o n n e c t i o n w i t h s t u d i e s o n p r e m a t u r ei n f a n t s in w h i c h h e m o l y t i c a n e m i a w a s a s s o c i a te d w i t h a ni n a d e q u a t e v i t a m i n E s t a t u s [3 ]. S u b s e q u e n t s t u d i e s h a v es h o w n t h a t s e c o n d a r y v i t a m i n E d e f i c i e n c y o c c u r s i np a t i e n t s w i t h n e u r o l o g i c a l a b n o r m a l i t i e s i n a s s o c i a t i o nw i t h g e n e r a li z e d f at m a l a b s o r p t i o n s y n d r o m e o f v a r i o u se t i o l o g i e s [ 3, 6 2 ]. L o w s e r u m v i t a m i n E l e v e l s a r e f o u n d i n

W h y is V i t a m i n E D e f ic i e n c y N o t C o m m o n inH u m a n sA s s t a t e d a b o v e , d e c a d e s a f t e r t h e d i s c o v e r y o f v i t a m i n

E , it s n e e d o r u s e i n h u m a n s r e m a i n e d u n c e r t a i n d u e t ot h e l a c k o f a d e f i n i t e c l in i c a l s y n d r o m e a t t r i b u t a b l e t o i tsd e f i c i en c y o r a b s e n c e o f a w i d e s p r e a d v i t a m i n E d e f i c i e n -c y . A d d i t i o n a l l y , i t i s d i f f i c u l t t o i n d u c e a d e f i c i e n c y i nh e a l t h y a d u l t s e x p e r i m e n t a l l y [3 2]. I n f o r m a t i o n a c c u m u -l a t e d o v e r t h e p a s t d e c a d e s s h o w s t h a t t h e p r e s e n c e o f( 1) t o c o p h e r o l r e g e n e r a t i o n s y s t e m s a n d ( 2) f u n c t i o n a l l yi n t e r d e p e n d e n t a n t i o x i d a n t s y s t e m s i s l a rg e l y re s p o n s i b l ef o r t h e a b s e n c e o f a w i d e s p r e a d v i t a m i n E d e f i c ie n c y a n dt h a t i t i s d i f f i c u l t t o d e p l e t e th e v i t a m i n i n h e a l t h y a d u l t s .

Tocopherol Regeneration SystemsI t h a s l o n g b e e n r e c o g n i z e d t h a t t h e e f fi c a cy o f a - t o -

c o p h e r o l i n v i v o c a n b e a u g m e n t e d b y a s c o r b i c a c i d [ 6 5] .S u b s e q u e n t s t u d i e s h a v e d e m o n s t r a t e d t h a t t h e a -t o -

2 9 6 J B i o me d Sc i 2 0 0 4 ; 1 1: 2 9 5 3 0 2 C h o w


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cophery l ch rom anoxy r ad ica l can be r eve r t ed to a - tocoph-erol and tha t the con vers ion is faci l i ta ted by ascorbic acidand g lu ta th ione (G SH) [6, 51 , 54] . Also , the red ucing s ta teo f a s corb ic ac id i s ma in ta ined by G S H -de penden t dehy -d roas co rba te r educ tas e and N A D H -s emidehydroas co r -ba te r educ tas e and tha t o f G S H by G S H d i s u l fide r educ-tase [14, 22] . Addi t ional ly , d ihydrol ipo ic acid , NA DH -c y t o c h r o m e b5 and ub iqu ino l may be invo lved in therege nera tion o f et- tocopherol [ 14, 36].

Funct ional ly Interdependent Ant ioxida nt Sys temsWhile the cel l i s cont inuous ly subjected to oxidat ive

s tress exer ted by a large var ie ty of chem ical , b io logical ,and phys ical agents in the cel lu lar environment , var iousant iox idant sys tems in the cel l are able to contro l or pre-vent the adverse ef fects of oxygen and i ts react ive in ter -med ia te s und er no rm al cond i t ions [12 , 1 4 ] . W hen theant iox idan t potent ia l i s we aken ed and/or oxida t ive s tressis increased , howev er , i r revers ib le dama ge to the cel l m ayoccur . The suscept ib i l i ty of a g iven organ or orga n sys temto ox ida t ive dama ge i s de te rmine d by the ove ra l l ba lancebe tw een the ex ten t o f ox ida t ive s t re s s and the an t iox ida n tcapab i l i ty [12 ] . M ajo r ce l lu la r an t iox idan t mechan i s msinclude (1) d i rect in teract ion with oxidants or oxid iz ingagents by ascorbic acid , GSH, and o ther red ucing agents;(2) scavenging of f ree radicals and s ingle t oxygen by v i ta-min E, ascorbic acid , caro tenoids , superoxide d ismutase ,and o ther scavengers ; (3) reduc t ion of hydroperoxid es byGS H peroxidases an d cata lase; (4) b indin g or removal oft rans i t ion metals by fer r i t in , t rans fer r in , ceru loplasmin,a lbumin , and o the r che la to r s ; (5 ) s epa ra t ion o r p r even t ionof react ive oxygen species f rom reaching the specif ic s i teo f ac t ion o r r eac t ing w i th e s s en t i al ce l lu la r compon en t s byme mb rane ba r r i e rs , and (6) r epa i r o f re s u l t ing damag e bydietary nutr ie nts a nd me tabol ic act iv i t ies [ 14].

Vi ta mi n E funct ion s c losely wi th o th er ant ioxid ant sys -tem s [12 , 14] . Ascorbic acid , GSH , l ipoic acid , and ubi-qu ino l , f o r example , a r e invo lved in the r egenera t ion o rr es to ra t ion o f v i t am in E . A lso , by r educ ing the hyd ro -pe rox ide fo rmed , s e l enoenzyme G S H perox idas e [61 ] andi ts funct iona l ly re la ted enzym es , GSH disulf ide reductaseand g lucos e -6 -phos pha te dehydrogenas e , augmen t thefunc t ion o f v i t amin E aga ins t pe rox ida t ive damage tom em bra ne l ip ids [ 17, 18] . Th e abi l i ty of the G SH peroxi-dase sys tem to respond to oxidat ive s t ress adapt ively orcom pensat iv ely seems to be respons ib le for the lack of s ig-n i f i can t accum ula t ion o f l ip id hyd roperox ides in the t i s-sues of v i tam in-E-de f ic ient and o the r oxidat ively s t ressedanim als [ 11 , 12 , 14 , 18] . By augm ent ing the a nt ioxid antfunc t ions o f v i t amin E , the G S H perox idase s ys tem a l so

comp lemen t s the tocophero l r egenera tion s ys tems in p r e -s e rv ing v i tam in E . A m ong the know n G S H perox idas es,phos pho l ip id hyd roperox ide G S H perox idase s eems to bethe m os t e f f ec tive one in p r even t ing pe rox ida t ive damageto m em bra ne l ip ids [37 , 75] .

W h y I s R R R a T o c o p h e r o l M o r e S u p e r i o rB i o l o g i c a ll y t h a n O t h e r I s o m e r s o fT o c o p h e r o l s ?W hile a ll i somers of tocoph erols are absorbed ef f ic ient-

ly , they d if fer widely in thei r b io logical ac t iv i t ies. T he b io-logical activity of tocophe rols is assessed by th eir relativ eabi l i ty to prev ent d ef ic iency sym ptom s such as fe ta lresorpt ion-ges ta t ion , ery throcyte hemolys is , and/or my-opa thy in rats [ 10, 77, 78]. Th e biologic al activ ity of vita-m in E is norm al ly expressed as in ternat ional uni ts re la t iveto tha t of all-rac-o.-tocopheryl ac etate. Th e rela tive values(IU/m g) are 1.00 for all-rac-o.- tocopheryl ace tate, 1.10 foralt-rac-ct- tocopherol, 1.36 for RR R-a -toc oph ery l aceta te,1 .49 for RRR -a- tocoph erol , 0 .89 for a l l - rac-a- tocopherytsuccinate , 1 .21 for RRR -ct- tocopheryl succinate , 0 .37 -0.75 for RRR-f3-tocopherol, 0.12 -0.28 for RR R-y -tocop h-erol , and 0 .01-0 .04 for RR R-8- tocopherol according tothe resorpt ion-ges ta t ion tes t [77 , 78] . RRR-7- tocopherolis the major source of tocopherols in a typical US die t[13].

A h igher v i t amin E ac t iv i ty o f RRR -a- tocophero l thanof o ther isom ers sugges ts that the RR R conf igurat ion ofthe phy ty l t a il i s needed fo r max im um b iopo tency , a -TTPrecognizes preferent ia l ly specif ic s t ructural features wi tha fu l ly methylated aromat ic r ing , a sa turated phytyl s idecha in , and a s t e r eochemica l RR R conf igu ra tion o f theme thyl groups branc hing of the s ide chain [69 , 70]. Byincorporat ing RRR-ct- tocopherol over o ther tocopherotsin to very- low-dens i ty l ipoprote ins (VLD L), which arethen secreted in to the p lasma, the process resul ts in thep re f e r en t i a l en r i chmen t o f low -dens i ty l ipop ro te in andhigh-dens i ty l ipoprote in wi th RRR-a- tocopherol in p las -ma. a-T TP also faci l ita tes the re turn of RRR-a- toc oph-e ro l to the l ive r from p las ma v ia h igh - and low -dens i tyl ipoprote ins . Absence of the t rans fer pro te in in pat ientsw i th f ami l i a l i so la ted v i t am in E de f i c iency , w h ich im pa i r sthe secret ion of tocopherol in to hepat ic l ipoprote ins , i srespons ib le for thei r ex tremely low vi tam in E s ta tus [41 ,44 , 72 , 73 ]. The s ec re to ry pa thw ay v ia nas cen t V LD Lfrom the l iver is cr i t ica l in mainta in ing tocopherol con-cen t r a t ions in p la s ma , and d i s c r imina t ion am ong the i s o-mer s by a -TTP occu r s du r ing hepa t i c s ec re t ion o f nas cen t

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VL DL [69 , 70 , 72 ]. Thu s , by r egu l a t i ng t he t r ans fe r / b i nd -i n g o f to c o p h e r o ts , a - T T P p l a ys a k e y r o l e i n d e t e r m i n i n gno t on l y the i r p l a s m a conce n t r a t i ons , bu t a l s o t he i r b i o -logical act ivi t ies .

W h a t H a p p e n s t o t h e T o c o p h e ro l s C o n s u m e dF o l l owi ng abs o rp t i on , t ocophero l s t aken u p by t h e l i v-

e r a r e e i t he r s t o red i n t he pa ren chym al ce ll s o r s ec re t edi n t o t h e b l o o d s t r e a m w i t h i n n a s c e n t V L D L . S o m e t o -c o p h e r o l s i n t h e V L D L m a y e n d u p i n l o w - d e n s it y l ip o -p ro t e i n by t he ac t i on o f li pop ro t e i n li pas e i n p la s m a . Thes cavenger r ecep t o r c l a s s B t ype I r ecep t o r , a m em brane-bo un d p ro t e i n , i s capab le o f tr an s fe r r i ng v i t am i n E i n t ot he ce l l , wh i l e t he ATP -b i nd i ng cas s e t t e t r an s po r t e r A1can ex c re t e v i t am i n E ou t o f t he ce l l [38 ]. Toc ophero l s i nl o w - d e n s it y l i p o p r o t e in m a y a g a in b e t a k e n u p b y t h e l i v e rv i a t he l ow-dens i t y l i pop ro t e i n ( ap o l i pop ro t e i n B / E) r e-cep t o r o r by non - re cep t o r - m e d i a t ed up t ake [41 , 69 ]. S om et o c o p h e r o ls i n a s s o c i a ti o n w i t h c h y l o m i c r o n s a n d V L D Lare t r ans fe r r ed t o pe r i phe ra l ce l ls an d h i gh -dens i t y li po -p ro t e i n du r i ng l i po l y si s by l i pop ro t e i n l ipas e . The t ocoph -e ro l s s ec re t ed a re e i t he r r ap i d l y r e t u rned f rom b l ood t ot he l i ve r o r ex c re t ed t o f eces. T hus , t he t ocophero l s con -s u m e d a r e e i t h e r s to r e d i n p a r e n c h y m a l c el ls o r m e t a b o -l i zed / exc re t ed in t o f eces o r u r i ne wi t h o r w i t ho u t exe r t i ngt h e i r f u n c ti o n s . T h e f a t e o f t o c o p h e r o l s c o n s u m e d i s s u m -m a r i zed be low:

Unchanged TocopherolsI n a d d i t i o n t o u n a b s o r b e d t o c o p h e r o l s , a p o r t i o n o f

a b s o r b e d t o c o p h e r o ls , n o t r e t u r n e d t o t h e l i v e r o r t a k e nup by o t he r o rgans f rom t h e c i r cu l a t i on , i s exc re t ed v i a t heb i le u n c h a n g e d a n d t h e n i n t o t h e fe ce s. T h e a m o u n t o func han ged t ocophero l s exc re t ed i n t o the f eces i s no rm al l yi nc reas ed , a s t he dos e i nc reas es .

One Electron Oxidation ProductsAfter exer t ing i t s funct ion as a f ree rad ical scavenger ,

t o c o p h e r o l i s fi rs t c o n v e r t e d t o t o c o p h e r y l c h r o m a n o x yrad i ca l . The ch rom anoxy r ad i ca l can r ead i l y be r eve r t edt o t ocophe ro l , and t he p roces s i s f ac i l it a t ed by s uch r educ-i ng agen t s a s GS H and as co rb i c ac i d i n a s s oc i a ti on wi t he n z y m e s y s t e m s ( s ee a b o v e ). S o m e t o c o p h e r y l c h r o m a -n o x y r a d ic a l s m a y b e q u e n c h e d t o f o r m d i m e r s o r t r im e r s .A s m a l l a m o u n t o f t h e d i m e r s a n d t r i m e r s o f a - t o c o p h e ro li s foun d in the l iver [23] .

Chroman Ring Opened ProductsT o c o p h e r y l c h r o m a n o x y r a d i c a ls c a n a ls o b e f u r t h e r

o x i d i z e d t o t o c o p h e r y l q u in o n e , a s m a l l a m o u n t o f w h i c hi s foun d i n t he l ive r [23 ]. The t ocop hery l qu i non e fo rm e dc a n b e c o n v e r t e d t o t o c o p h e r y l h y d r o q u i n o n e , a n d t h er e a c t i o n i s c a t a l y z e d b y a N A D P H - c y ~ o c h r o m e P - 4 5 0redu ctase [33] . Bou nd or co njug ated c~ .- tocopherylh y d r o -qu i none can be s ec re t ed i n t o t he b i l e and e l i m i na t ed i nt he f eces [ 19 ]. Ano t h e r po r t i on o f a - t ocophe ry l hyd roqu i -n o n e m a y f u r t h e r b e m e t a b o l i z e d , b y s i d e c h a i n s h o r t e n -ing v ia [3-oxidat ion , to form a- tocopheronic acid (or to-c o p h e r o n o l a c t o n e ) w h i c h is s u b s e q u e n t ly c o n j u g a t e d a n dexcre t ed i n t o u r i ne [19 ] . A s m al l am oun t o f c t - t ocoph -e r o n i c a c id i s f o u n d i n t h e u r i n e o f r a b b it s a n d h u m a n sa f t e r adm i n i s t r a t i on o f l a rge dos es o f a - t ocoph ero l [60 ].N e i t h e r a - t o c o p h e r y l q u i n o n e n o r a - t o c o p h er y l h y d r o q u i -non e i s conv er t ed t o a - t ocophe ro l i n v i vo [ 19 ].

Side Chain Shortened Products without OpeningChroman RingS everal u r i na ry m e t abo l i t e s o f tocophero l s w i t h t he s i de

cha i n s ho r t ened a re fo rm ed i n t he l i ve r d ir ec t ly f rom a s i decha i n deg rada t i on o f t ocophero l s w i t hou t ox i da t i ve s p l it -t i ng o f t he ch r om an r i ng [38 ]. The s i de cha i n o f t oc oph ero l si s in i t i a lly hydrox ylated v ia c0-hydroxylation, and the reac-t i on i s ca ta l yzed by t he cy t och ro m e P -4503A fam i l y o fenzym es . Af t e r hyd roxy l a t i on , t he s i de cha i n o f t ocopher -o l s is shor ten ed v ia [3-oxidation f ro m 16 carbo ns to threeca rbons . I t appea r s t ha t t he p roduc t , 2 , 5 , 7 ,8 - t e t r am et h -y l- 1 2 - ca rboxye t hy l )-6 -hyd roxych rom an i n s t ead o f a - t o-cophero n i c ac id , i s t he m a j o r u r i na ry m e t abo l i t e o f a- t o-coph erol [58] . S ince 2 ,5 ,7 ,8- te t ramethyl - l (2 -carbo xyeth-y l ) -6 -hyd roxych rom an can be ox i d i zed t o fo rm a - t ocoph -e ron i c ac i d , wh e t he r t he l a t te r com pou nd i s an a r t i f ac t o ran auth ent ic m etabo l i t e i s unc er ta in . S imi lar ly , 2 ,5 ,8- tr i-m e t hy l -2 (2 - ca rboxye t hy l ) -6 -hyd roxych rom an , 2 , 7 ,8 - tr i -m e t hy l -2 (2 - ca rboxye t hy l ) -6 -hyd roxych rom an ,an d 2 ,8-d i -m e t hy l -2 (2 - ca rboxye t hy l ) -6 -hyd roxych rom an have beenident i f i e d as the pr inc ipal ur ina ry m etabo l i t es for 13-,7 - and8-toco phero ls , resp ect ive ly [8, 38, 76].

T h e i d e n t if i c a ti o n o f t h e s e u r i n a r y m e t a b o l i te s p r o -v i d e s a b e t t e r u n d e r s t a n d i n g o f t h e m e t a b o l i c f a te s o f v a r -i ous t ocophero l s cons um ed . In fo rm at i on ava i l ab l e s ug -ges ts tha t t h e s i de -cha i n - s ho r t ened p rodu c t s , w i t h t hec h r o m a n r i n g i n ta c t , a r e t h e m a j o r u r i n a r y m e t a b o l i te s o ft ocophero l s ab s o rbed , e s pec i a l ly when a l a rge dos e i s con -s u m e d . C o u p l e d w i t h i t s p re f e r e n ti a l b o u n d i n g t o R R R -a- t ocophero l , a -TT P a l s o s heds li gh ts on t he d i f f e ren t ia lb i o l og ica l ac ti v i ti e s o f va r i ous i s om ers o f v i t am i n E w h i cha re s i m i l a rl y abs o rbed .

298 J Biomed Sci 2004; 11:295 302 Ch ow


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H o w M a y V i t a m i n E F u n c t io n a t t h e T i s s u eL e v e lAl t hou gh t he s c i en t if i c r a t iona l e , ep i dem i o l og i ca l da t a ,

a n d r e t r o sp e c t i v e s t u d ie s l a rg e ly s u p p o r t t h e a s s u m p t i o nt ha t an i nc reas ed i n t ake o f v i t am i n E i s a s soc i a t ed wi t h areduced r i s k o f degenera t i ve d i s eas es , p ro s pec t i ve , r an -dom i zed , p l acebo -co n t ro l l ed t r ia l s hav e f a i l ed t o ve r i fy acon s i s ten t benef i t [21 , 43 , 47 , 48 , 64 , 74] . Based on th et o t a l i ty o f ava i l ab le s c i en t i f ic ev i dence , t he U S F oo d an dD r u g A d m i n i s t r a t i o n d i d n o t a p p r o v e t h e h e a l th c l a im sas s oc i a t ed wi t h v i t am i n E i n t ake a nd r i s k o f cance r o r ca r-d i ovas cu l a r d i s eas e . S i m i l a r l y , t he r ecen t P ane l on Di -e t a r y A n t i o x i d a n t s o f t h e U S F o o d N u t r i t i o n B o a r d d i dno t r ecom m end an i nc reas e i n i t s da i l y a l l owance . Ina d d i t i o n t o t h e i n c o n c l u si v e f i n d in g s f r o m m o r e r e c e n tp ros pec t i ve p l acebo -con t ro l l ed t r i a l s , a l ack o f under -s t a n d i n g o f t h e m o d e o f a c ti o n o f v i t a m i n E a t t h e t i ss u elevel i s a l so respon s ib le .W h i l e a n u m b e r o f b i o c h e m i c a l a b n o r m a l i ti e s a r e a s so -c i a t e d w i t h v i t a m i n E d e f i c ie n c y , t h e m e c h a n i s m b yw h i c h v i t a m i n E p r e v e n t s v a r io u s m e t a b o l i c a n d p a t h o -l og ica l le s i ons is no t ye t c l ear . A m ed i a t i n g ro l e o f v i t am i nE i n m i t o c h o n d r i a l s u p e r o x i d e g e n e r a t io n , h o w e v e r , m a yexp l a i n how t he v i t am i n exe r t s i ts ac t i on a t t he t i s sue l ev -e l. Th e m i t och ond r i on , wh i ch u t i li zes ove r 85 o f oxy -gen , i s t he m a j o r s i t e o f s upe rox i de gene ra t i on , wh i l es uperox i de p lays a cen t r a l ro le i n t he fo rm a t i on o f r eac t i veoxygen s pec i es , i nc l ud i ng hyd rogen pe rox i de , hyd roxy lr ad i ca l , and pe roxyn i t r i t e [63 ] . In t e res t i ng l y , t he m i t o -c h o n d r i o n h a s t h e h i g h e s t c o n c e n t r a t i o n o f v i t a m i n E ,a n d d i s r u p t i o n o f t h e m i t o c h o n d r i a I s tr u c t u r e i s o n e o f t h eea r l i e s t even t s i n t he s ke l e t a l m us c l e o f v i t am i n -E-de f i -c i en t an i m a l s [67] . R ecen t l y , d i e t a ry v i t am i n E has beens h o w n t o r e d u c e t h e m i t o c h o n d r i a l s u p e r o x id e g e n e r a t io n[20 , 45 ]. D i e t a ry v i t am i n E m ay a l s o r educe t he l eve ls o fs u p e r o x i d e b y s ta b il iz i n g m i t o c h o n d r i a l m e m b r a n e s a n ds caveng i ng t he s upe rox i de gene ra t ed . B y r educ i ng t hegenera t i on / l eve l s o f s upe rox i de , d i e t a ry v i t am i n E no to n l y a t te n u a t e s o x i d a t iv e d a m a g e , b u t m a y a l s o m e d i a t et he e xp res s i on and / o r ac t i va t i on o f r edox - s ens i ti ve b io l og -i ca l m od i f i e r s v i t a l fo r i m por t a n t ce l l u la r even t s [ 16] .

H o w M a y V i t a m i n E F u n c ti o n a s a n A n t i o x i d a n tin vivoR eac t i ve oxygen / n i t rogen s pec i es m ay r eac t w i t h ce l l u -

l a r c o m p o n e n t s w i th r e s u l ta n t d e g r a d a t i o n a n d / o r i n a ct i-vat ion of essent ia l ce l lu lar co ns t i tu ents [ 12 , 27 , 31 , 80] .V i t a m i n E c a n r e a c t m o r e r a p i d l y w i t h p e r o x y r a d ic a l ss eve ra l o rde r s o f m agn i t ude f a s t e r t han wi t h acy l l i p i d s

and t hus p re ven t s pe ro x i da t i on t i s sue dam age [40 ]. A l so ,v i t a m i n E m a y e x e r t i ts a n t i o x i d a n t f u n c t i o n b y l i m i t in gt he gene ra t i on and / o r l eve l s o f s upe rox i de and r e l a t edreac t ive oxyg en/n i t roge n species [16, 20 , 45]. In the pres -e n c e o f t r a n s i ti o n m e t a l i o n s, s u p e r o x i d e m a y b e c o n -ver te d to h ighly react ive hyd roxy l rad ical s [50 , 79] . Also ,s upe rox i de can r eac t r ead i l y w i t h n i t r i c ox i de t o fo rmperoxy n i t r i t e [63 ]. P e roxyn i t r i t e and hyd roxy l r ad i ca l s a r et he m os t r eac t i ve f r ee r ad ica l s t ha t m ay oc cu r i n b i o l og ica ls y s t em s . Add i t iona l l y , s upe rox i de m a y r e l ease i ron f romi t s pro te in c om plex [29 , 42 , 49]. T he ce l lu lar l ab i le i ron orf r ee iron a s s oc i a t ed wi t h l ow m o l ecu l e m as s has t he p o t en -t i a l t o pa r t i c i pa t e i n r edox cyc l i ng and ca t a l yze t he fo rm a -t i on o f hyd roxy l r ad i ca ls f rom s uperox i de / hyd rog en pe r -ox i de [39 , 42 , 49 ]. O n t he o t he r han d , t he s t a te an d l eve l so f l ab i le i r o n c a n b e m o d i f i e d b y o x i d a n t s o r r e d u c t a n t sact ing on cel l i ron sources , such as fer r i t in .

I t h a s l o n g b e e n r e c o g n i z e d th a t d i e t a ry v i t a m i n Ea l t e rs t he i ron m e t abo l i s m and p ro t ec t s aga i n s t ox i da t i vedam age r e s u l t i ng f rom i ron ove r l oad [9, 26 , 56] . The p ro -t ec t i ve e ff ec t can now be pa r t l y a t t r ibu t ab l e t o t he ab i l it yo f d i e t a ry v i t am i n E t o l i m i t t he gene ra t i on and / o r l eve l o fs uperox i de . B y r educ i ng t he gene ra t i on and / o r l eve l s o fs uperox i de , v i t am i n E no t on l y r educes t he l eve ls o f ha rm -fu l f r ee r ad ica l s , bu t a l so l i m i t s t he r e l eas e o f i ron f rom i t sp ro t e i n com pl ex . In co l l abo ra t i on wi t h h i ghe r r a t e s o fm i t o cho nd r i a l s upe rox i de gene ra t i on , h i ghe r leve l s o f l a-b i l e iron an d ox i da t i on p rodu c t s were found i n t he t i ss ueso f r a t s f ed a l ow v i t am i n E d i e t [35 ]. Add i t i ona l ly , t ran s -g e n ic m i c e o v e r e x p r e s si n g m a n g a n e s e s u p e r o x i d e d i s m u -t as e had l ower t is s ue l eve ls o f lab i le i ron and ox i da t i onp r o d u c t s , w h i l e m a n g a n e s e s u p e r o x i d e k n o c k o u t m i c ehad h i ghe r t is s ue l eve ls o f lab i l e i ron and ox i da t i on p rod -uc t s [35 ]. Th es e f i nd i ngs a l s o s uppo r t t he v i ew t ha t s upe r -ox i de an d f r ee i ron p l ay a key ro l e in i n i t i a t i ng ox i da t i vet i s sue dam a ge .

T h u s , v i t a m i n E m a y p r e v e n t o x i d a t i v e d a m a g e o rexe r t i ts an t i ox i dan t func t i on b y (1 ) d i r ec tl y s caveng i ngox i dan t s / f r ee r ad ica l s and (2) down regu l a t i ng m i t oc hon -d r i a l s upe rox i de gene ra t i on wh i ch i n t u rn r educes t he fo r -m a t i on o f pe roxyn i t r i t e and r e l eas e o f l ab il e i ron f rom i tsp ro t e i n com pl ex . B y r educ i ng s uperox i de and ava i l ab l el ab il e i ron , t he pos s i b i li t y o f hyd roxy l r ad i ca l fo rm a t i on i sa l s o reduce d .

H o w M a y V i t a m i n E A c t a s a B io l o g ic a l R e s p o n s eM o d i f i e rS i nce no t a l l t he b i o l og i ca l e f f ec t s can be exp l a i ned

bas ed on i t s an t i ox i dan t p rope r t y , v i t am i n E m ay a l s of u n c t i o n a s a b i ol o g ic a l re s p o n s e m o d i f i e r i n d e p e n d e n t o f

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i ts an t i ox i dan t func t i on [71 ]. R ecen t advances i n m o l ecu -l a r b i o logy and g enom i c t echn i que s have l ed t o t he d i s cov -e ry o f nov e l v i t am i n -E -s ens i t i ve genes and s i gna l t r an s -duc t ion pathw ays [57] . RRR-o~-tocopherol for exam plehas b een s hown t o r egu l a t e key ce ll s i gna l ing func t i onsp ro t e i n k i nas e C ac t iv i t y and va s cu l a r s m oo t h m us c l e ce llg rowt h by m e cha n i s m s un re l a t ed t o i t s an t i ox i dan t [66 ].A l s o R R R -o - t ocophero l m o du l a t e s t he exp res s i on o f t hehepa t i c co l lagen ~ 1 gene ~ -TT P gene a - t ropom ys i n genea n d c o ll a g en a s e g e n e a n d d i m i n i s h e s a d h e s i o n m o l e c u l eco l lagenas e and s cavenger r ecep t o r exp res s i on and i n -c reas es c onne c t i ve t is s ue g row t h f ac t o r e xp res s i on [2 ].

W h i l e t h e m e c h a n i s m b y w h i c h v i t a m i n E m e d i a t e scel l -s ignal ing func t ions i s no t yet c lear a l t era t ion of oxi-da t i ve s t r e s s o r r edox hom eos t as i s m ay be one o f t he ha ll -m a rks o f the p roces s es t ha t r egu l a t e gene t r ans c r i p t i on i nphys i o l ogy and pa t hoph ys i o l ogy [30 ]. C ha nges i n t h e pa t -t e rn o fgen e exp res s i on t h rough r edox - s ens i t i ve r egu l a t o ryt r ans c r i p t i on f ac t o r s a r e c ruc i a l com p one n t s o f t he m a-ch i ne ry t ha t de t e rm i nes ce l l u l a r r e s pons es t o ox i da t i vecond i t i ons . F o r exam p l e t he tr ans c r i p t i on f ac t o r s nuc l ea rf ac t o r -kappaB a nd hypox i a - i nduc i b l e f ac to r - 1a are d i rect -l y i n f l uenced by r eac t i ve s pec i es and p ro i n f l am m at o rys i gna l s [30 ]. M aj o r s i gna li ng t r ans du c t i on p a t hways t ha tm ay be i nvo l ved i n hyperox i a i nc l ude t he m i t ogen -ac t i -va t ed p ro t e i n k i nas es ac t i va t o r p ro t e i n - l and nuc l ea rf ac t o r -kappaB wh i ch converge u l t i m a t e l y t o t he exp res -s i on o f a r ange o f s t re s s r e s pons e genes cy t ok i nes andgrow th factors [46] . Also oxid at ive s t ress or redox s ta tes eem s t o have a dua l e f f ec t on t he ac t i va t i on o f nuc l ea rfactor-ka ppaB [5] .

R egu l a t i on o f s i gnal t r an s du c t i on an d gene exp res s i oni s a m u l t i f ace t ed p roces s i nvo l v i ng l i gands r ecep t o r s ands econd m es s enger s t ha t t r i gge r cas cades o f p ro t e i n k i nas esa n d p h o s p h a t a s e s a n d p r o p a g a t e t h e s i g na l t o t h e n u c l e u st o a l t e r t he gene exp res s i on . R edox -ba s ed r egu l a t o ry pa t h -

ways p rov i de add i t i ona l m ean s o f ga t ing s igna l t r an s duc-t i on and r edox -bas ed r egu l a t ion o f gene exp res s i one m e r g e s a s a f u n d a m e n t a l r e g u la t o ry m e c h a n i s m i n l iv i n gce ll s [55 ]. T he i n t r ace l lu l a r p rod uc t i on o f r eac t i ve oxygen /n i t ro g e n s p e c ie s s e e m s to b e o f f u n d a m e n t a l i m p o r t a n c ein cell p ro l i fera t ion d i f fere nt ia t ion apop tos i s ne cros i svas cu l a r hyperg l ycem i a p l a t e l e t adhes i on / agg rega t i ont h rom b os i s t um or ang i ogenesi s an d o t he r i m por t an t ce l-l u l a r even t s [7 25 52 68 ]. Thu s by r educ i ng t he gene ra -t i on an d / o r l eve l s o f s upe rox i de an d o t he r r eac t i ve oxy -g e n / n it r o g e n s p ec ie s d i e ta r y v i t a m i n E m a y m o d u l a t e t h eac t i va t i on a nd / o r e xp res s i on o f r edox - s ens i t i ve b io l og ica lr e s pons e m od i f i e r s and m ay t he reby a t t enu a t e t he ce l l u la reven t s l ead i ng t o t he ons e t o f ca rd i ovas cu l a r d i s eas escance r and ag i ng and neu rod egen era t i ve d i s eas es [16 ].H o w e v e r w h e t h e r t h is m e d i a t i n g r o le o f v it a m i n E i n t h ece l l - s i gna l i ng even t s i s i ndependen t o f o r s econdary t oan t i ox i da n t func t i on o r changes i n r edox s t a te r em ai ns t obe e l uc i da t ed .

o n c l u d i n g R e m a r k sW hi l e the i n t e res t i n the ro l e o f v i t am i n E i n p reven t -

i ng t he pa t hogen es i s o f degen era t i ve d i seas e r em a i ns h i ghrecen t p ro s pec t i ve r ando m i ze d p l acebo -con t ro l l ed t r ia l shave f a i led t o ve r i fy a con s i s t en t bene f i t . I n fo rm at i ona c c u m u l a t e d o v e r t h e p a s t d e c a d e s h a s c o n f i r m e d t h ee s s e nt ia l it y o f v i t a m i n E f o r h u m a n s a n d p r o v i d e d a b e t -t e r un der s t an d i ng o f it s b io l og ica l func t i on and t he m e t a -bo l i c f a t e . The ab i l i t y o f d i e t a ry v i t am i n E t o m ed i a t es uperox i de gene ra t i on / l eve l a f fo rd s a pos s i b l e m ode o fac t i on o f t he v i t am i n a t t he t i ss ue l eve l s. More s t ud i es a r eneed ed t o de t e rm i ne m o re p rec i s e ly t he bene f i t s o f v i ta -m i n E i n h u m a n h e a l t h a n d i t s m o d e o f a ct i o n a t th e t i ss u elevels.

R e f e r e n c e s1 A r i t a M , S a t o , Y , M i ya t a A , T a ba b e T , T a ka ha -sh i E , K a yd e n I t J , A r a i H , I noue K . H um a n

a - t oc ophe r o l t r a ns f e r p r o t e i n : G e ne s t r uc t u r ea nd c h r omo som a l loc a l i z a ti on . B i oc he m J 305 :437- 443 ; 1995.2 A z z i A , R i c c i a re l l i R , Z i ngg JM . N on - a n t i ox i -da n t m ol e c u l a r f unc t i ons o f a l pha - t oc opbe r o l( v i t a mi n E ) . F E BS L e t t 51 9 : 8 - 10 ; 2002 .

3 B i e r i JG , F a r r e l l P M . V i t a m i n E . V i t a m H or m34:31-75; 1976.

4 B u r t o n G W , T r a b e r M G . V i t a m i n E : A n t i o x i-da n t a c t i v it y , b i ok i ne t i c s , a nd b i oa va i l a b i li t y .A nn u Re v N u t r 10 : 357- 380 ; 1990.

5 Byun M S , J e on K I , Cho i JW, S h i m JY , JueD M . D ua l e f f e c t o f ox i da t i ve s t r e s s on N F - ka p-pa kB a c t i va t i on i n H e L a c e l l s . E xp M ol M e d34 : 332- 339 ; 2002 .

6 C h a rt A C , T r a n K , R a y n o r T , G a n z P R , C h o wC K . R e g e n e r a t io n o f v i t a m i n E i n h u m a np l a t e l e t s . J B i o l Che m 266 : 17290- 17295 ;1991.

7 Ch i a r ug i P . Re a c t i ve oxyge n spe c i e s a s me d i a -t o r s o f c el l a dhe s i on . I t al J B i oc he m 52 : 28- 32 ;2003.8 C h i k u S , H a m a m u r a K , N a k a m u r a T . N o v e lur inary metabol i te of ~5- tocopherol in r a ts . JL i p i d Re s 25 : 40- 48 ; 1984 .

9 C h o u A C , B r o u n G O , F i tc h C D J r . A b n o r m a l i -t i e s o f i r on me t a bo l i sm a nd e r y t h r opo i e se s i nv i t a mi n E - de f i c i e n t r a bb i t s . B l ood 52 : 18 195 ;1978.

3 0 0 J B i o m e d S ci 2 0 0 4 ; i 1 : 2 9 5- 3 0 2 C h o w


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l0 Chow CK. Increased activity of pyruvate ki-nase in plasma of vitamin E-deficient rats. JNutr 105:1221-1224;1975.11 Chow CK. Biochemical responses in the lungsof ozone-tolerant rats. Nature 260:721-722;1976.12 Chow CK. Nutritional influence in cellular an-tioxidant defense systems. Am J Clin Nutr 32:1066-1081;1979.13 Chow CK. Vitamin E and blood. World RevNutr Diet 45:133-166; 1985.14 Chow CK. Vitamin E and oxidative stress. FreeRadic Biol Med 11:215-232; 1991.15 Chow CK. Vitamin E. In: Rucker RB, SuttieJW, McCormick DB, Machlin LJ, eds. Hand-book of Vitamins, ed 3. New York, MarcelDekker, 165-197; 2001.16 Chow CK. Vitamin E regulation of mitochon-drial superoxide. Biol Signals Recept 10:112-124;2001.17 Chow CK, Tappel AL. An enzymatic protec-tive mechanism against lipid peroxidationdamage to lungs of ozone-exposed rats. Lipids7:518-524;I972.18 Chow CK, Reddy K, Tappel AL. Eft~ct of

dietary vitamin E on the activities of gluta-thione peroxidase system in rat tissue. J Nutr103:618-624;1973.19 Chow CK, Draper HH, Csallany AS, Chiu M.The metabolism of 14C-u-tocopheryl quinoneand 14C-ct-tocopherylhydroquinone. Lipids 2:390-396; 1967.20 Chow CK, Ibrahim W, Wei Z, Chan AC. Vita-min E regulates mitochondrial hydrogen perox-ide generation. Free Radic Biol Med 27:580-587;1999.21 Clarke R, Armitage J. Antioxidant vitaminsand risk of cardiovascular disease: Review oflarge-scale randomised trials. CardiovascDrugs Ther 16:411-415;2002.22 Diliberto E Jr, Dean G, Carter C, Allen PL.Tissue, subceilular, and submitochondriaI dis-tributions of semidehydroascorbate reductase:Possible role of semidehydroascorbate reduc-tase in cofactor regeneration. J Neurochem 39:563-568;1982.23 Draper HH, CsaIlany A. Metabolism and flanc-tion of vitamin E. Fed Proc 28:1690-1695;1969.24 Evans HM, Bishop KS. On the existence of ahitherto unrecognized dietary factor essentialfor reproduction. Science 56:650-651; 1922.25 Finkel T. Oxidant signals and oxidative stress.Curr Opin Cell Biol 5:247-254;2003.26 Fraga CG, Oteiza PI. Iron toxicity and antioxi-dant nutrients. Toxicology 180:23-32;2002.27 Freeman BA, Crapo JD. Biology of disease:Free radicals and tissue injury. Lab Invest 47:412-426;1982.28 Gabsi S, Gouider-Khouja N, Belal S, Fki M,Kefi M, Turki I, Ben-Hamida M, Kayden H,Mebazaa R, Hentati F. Effect of vitamin E sup-plementation in patients with ataxia with vita-min E deficiency. Enr J Neurol 8:477-481;2001.29 Gutteridge JM. Iron promoters of the Fentonreaction and lipid peroxidation can be releasedfrom hemoglobin by peroxide. FEBS Lett 201:291-295; 1986.

30 Haddad JJ. Antioxidant and prooxidant mech-anisms in the regulation of redox(y)-sensitivetranscription factors. Cell Signal 14:879-897;2002.31 Halliwell B. Oxidants and human disease:Some new concepts. FASEB J I:358-364;1987.32 Harmon EM, Witting LA, Horwitt MK. Rela-tive rates of depletion of alpha-tocopherol andtinoleic acid after feeding polyunsaturated fats.Am J Clin Nutr 18:243-248; 1966.33 Hayashi T, Kanetoshi A, Nakamura M, Tamu-ra M, Shirahama H. Reduction of alpha-to-copherolquinone to alpha-tocopherolhydroqui-none in rat hepatocytes. Biochem Pharmacol44:489-493;1992.34 Hentati A, Deng HX, Hung WY, Nayer M,Ahmed MG, He X, Tim R, Stumpf DA, Siddi-que T. Human alpha-tocopherol transfer pro-tein: Gene structure and mutations in familialvitamin E deficiency. Ann Neurol 39:295-300;1996.35 Ibrahim W, Chow CK. Unpublished results.36 Ibrahim WH, Bhagavan HN, Chopra RK,Chow CK. Dietary coenzyme Q 10 and vitaminE alter the status of these compounds in rat tis-sues and mitochondria. J Nutr 130:2343-2348;2000.37 Imai H, Nakagawa Y. Biological significance ofphospholipid hydroperoxide glutathione per-oxidase (PHGPx, GPx4) in mammalian cells.Free Radic Biol Med 34:145-169;2003.38 Jialal I, Traber M, Devaraj S. Is there a vitaminE paradox? Curr Opin Lipidol 12:49-53;2001.39 Kakhlon O, Ioav Cabantchik Z. The labile ironpool: Characterization, measurement, and par-ticipation in cellular processes. Free Radic BiolMed 33:I037-1046;2002.40 Kamal-Eldin A, Appetqvist LA. The chemistryand antioxidant properties of tocopherols andtocotrienols. Lipids 31:671-701; 1996.41 Kayden HJ, Traber MG. Absorption, lipopro-tein transport, and regulation of plasma con-centrations of vitamin E in humans. J LipidRes 34:343-358;1993.42 Keyer K, Imlay JA. Superoxide acceleratesDNA damage by elevating free iron Ievels. ProcNatt Acad Sci USA 93:13635-t 3640; 1996.43 Kline K, Lawson KA, Yu W, Sanders BG. Vita-min E and breast cancer prevention: Currentstatus and future potential. J Mammary GlandBiol Neoplasia 8:91 102;2003.44 Kohlschiitter A, Hiibner C, Jansen W, LindnerSG. A treatable familial neuromyopathy withvitamin E deficiency, normal absorption, andevidence of increased consumption of vitaminE. J Inherit Metab Dis 11 : 149-152; 1988.45 Lass A, Sohal RS. Effect of coenzyme Q(10)and alpha-tocopherol content of mitochondriaon the production of superoxide anion radicals.FASEB J 14:87-94;2000.46 Lee PJ, Choi AM. Pathways of cell signaling inhyperoxia. Free Radic Biol Med 35:341-350;2003.47 Manson JE, Bassnk SS, Stampfer MJ. Doesvitamin E supplementation prevent cardiovas-cular events? J Womens Health (Larchmt) i2:123-136;2003.

48 Meagher EA. Treatment of atherosclerosis inthe new millennium: Is there a role for vitaminE? Prey CardioI 6:85-90;2003.49 Minott i G. Sources and role of iron in lipidperoxidation. Chem Res Toxicol 6:134-146;1993.50 Minotti G, Aust SD. The requirement for iron(III) in the initiation of lipid peroxidation byiron (II) and hydrogen peroxide. J Biol Chem262:1098-1 i04;I 987.51 Niki E, Tsuchiya J, Tanimura R, Kamiya Y.Regeneration of vitamin E from alpha-chroma-noxy radical by glutathione and vitamin C.Chem Lett 6:789-792;1982.52 O'Donnell VB. Free radicals and lipid signalingin endothelial cells. Antioxid Redox Signal 5:195-200;2003.53 Quahchi K, Arita M, Kayden H J, Hentati F,Hamida MB, Sokol R, Arai H, Inoue IG Man-del IL, Koenig M. Ataxia with isolated vitaminE deficiency is caused by mutation in the n-tocopherol transfer protein. Nat Genet 9:141-145;I995.54 Packer JE, Slater TF, Wilson RL. Direct obser-vation of a free radical interaction betweenvitamin E and vitamin C. Nature 278:737-738;1979.55 Pfeilschifter J, Eberhardt W, Huwiler A. Nitricoxide and mechanisms of redox signaling. JAm Soc NephroI 14(8 suppl 3):S237- 240;2003.56 Poli G, Albano E, Biasi F, Cecchini G, CariniR, Bellomo G, Dianzani MU. Lipid peroxida-tion stimulated by carbon tetrachloride or ironand hepato%e death: Protective effect of vita-min E. Eur J Biochem 59:449-455;1975.57 Rimbach G, Minihane AM, Majewicz J, Fi-scher A, Pallauf J, Virgli F, Weinberg PD. Reg-ulation of cell signalling by vitamin E. ProcNutr Soc 61:415-425;2002.58 Schultz M, Leist M, Petrzika M, Gassmann B,Brigelius-Flohe R. Novel urinary metabolite ofc~- ocopherol, 2,5,7,8 tetramethyl-2(2'-car-boxyethyl)-6-hydroxychroman, as an indicatorof an adequate vitamin E supply? Am J ClinNutr 62(6 Suppl): 1527S- 1534S; 1995.59 Scott ML. Studies on vitamin E and related fac-tors in nutrition and metabolism. In: DeLucaHF, Suttie JW, eds. The Fat-Soluble Vitamins.Madison, University of Wisconsin Press, 355-368; 1969.60 Simon EJ, Eisengart A, Sundheim L, MilhoratAT. The metabolism of vitamin E. II. Purifica-tion and characterization of urinary metabo-lites of a-tocopherol. J Biol Chem 221:807-817;1956.

61 Smith P, Tappel AL, Chow CK. Glutathioneperoxidase activity as a function of dietary sele-nomethionine. Nature 247:392-393;1974.62 Sokol RJ. Vitamin E deficiency and neurologi-cal disease. Annu Rev Nutr 8:351-373; 1988.63 Squadrito GL, Pryor WA. Oxidative chemistryof nitric oxide: The roles of superoxide, peroxy-nitrite, and carbon dioxide. Free Radic BiolMed 25:392-403;1998.64 Sung L, Greenberg ML, Koren G, TomlinsonGA, Tong A, Malkin D, Feldman BM. VitaminE: The evidence for multiple roles in cancer.Nntr Cancer 46:1-14;2003.

Biological Fun ct ion s of Vi tam in E J Biomed Sci 2004;11:295-302 301


8/8

65 Tappel AL. Will antioxidant nutrients slowaging process? Geriatrics 23:97-105; 1968.66 Tasinato A, Boscoboinik D, Bartoli GM, Ma-roni P, Azzi A. d-Alpha-tocopherol inhibitionof vascular smooth muscle cell proliferationoccurs at physiological concentrations, corre-lates with protein kinase C inhibition, and isindependent of its antioxidant properties. ProcNatl Acad Sci USA 92:12190-12194;1995.67 Thomas PK, Cooper JM, King RH, WorkmanJM, Schapira AH, Sampson MA, Muller DP:Myopathy in vitamin E deficient rats: Musclefiber necrosis associated with disturbances ofmitochondrial function. J Anat 183:451-461;

1993.68 Touyz RM. Recent advances in intracellularsignalling in hypertension. Curr Opin NephrolHypertens 12:165-174;2003.69 Traber MG. Determinations of plasma vitaminE concentrations. Free Radic Biol Med 16:229-239; 1994.70 Traber MG, Kayden HJ. Preferential incorpo-ration of a-tocopherot vs. 7-tocopheml in hu-man lipoproteins. Am J Clin Nutr 49:517-526;1989.

71 Traber MG, Packer L. Vitamin E: Beyond an-tioxidant function. Am J Clin Nutr 62(6Suppl): 1501 S- 1509S; 1995.72 Traber MG, Bin-ton GW, Ingold KU, KaydentIJ. RRR- and SRR-a-tocopherols are secretedwithout discrimination in human chylomi-crons, but RRR-a-tocopherol is preferentiallysecreted in very low density lipoproteins. J Lip-id Res 31:675-685;1990.73 Traber MG, Sokol RJ, Kohlschtitter A, KaydenH J. Impaired discrimination between stereo-isomers of a-tocopherol in patients with famil-ial isolated vitamin E deficiency. J Lipid Res34:201-210;1993~74 Upston JM, Kritharides L, Stocker R. The roleof vitamin E in atherosclerosis. Prog Lipid Res42:405-422;2003.75 Ursini F, Maiorino M, Gregolin C. t-he sele-noenzyme phospholipid hydroperoxide gluta-thione peroxidase. Biochim Biophys Acta 839:62-70;1985.

76 Wechter WJ, Kantoci D, Murry ED Jr, D Ami-co DC, Jung ME, Wang Wt-I. A new endoge-nous natriuretic factor: LLU-a. Proc Natl AcadSci USA 93:6002-6007; 1996.77 Weiser H, Vecchi M. Stereoisomers of e.-to-copheryl acetate. II. Biopotencies of all eightstereoisomers, individually or in mixtures, asdetermined by rat resorption-gestation tests.Int J Vitam Nutr Res 52:351-370;1982.78 Weiser H, Vecehi M, Schlachter M. Stereoiso-mers of alpha-tocopheryl acetate. IV. USPunits and alpha-tocopherol equivalents of all-rac-, 2-ambo- and RRR-alpha-tocopherol eval-uated by simultaneous determination of re-sorption-gestation, myopathy and liver storagecapacity in rats. Int J Vitam Nutr Res 56:45-56;1986.79 Welch KD, Davis TZ, Van Eden ME, Aust SD.Deleterious iron-mediated oxidation ofbiomo-lecules. Free Radic Biol Med 32:577-583;2002.80 Yu BP. Cellular defense against damage fromreactive oxygen species. Physiol Rev 74:139-162; 1994~

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