Arch Pharm Res Vol 28, No 3, 249-268, 2005 ~rt~i~ez of ~armata ]~e~eart~ http://apr.psk.or.kr Induction of Phase I II and III Drug Metabolism/Transport by Xenobiotics Changjiang Xu Christina Yong-Tao Li and Ah -Ng Tony Kong Department of Pharmaceutics, Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA Rutgers, The State University of New Jersey, Received No vem ber 18, 2004) Drug metabolizing enzym es DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that reg- ulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 Nrf2) have been shown to be the key mediators of drug-i nduced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR , which dimerizes with the AhR nuclear translocator Arnt), in response to many polycyclic aromatic hydrocarbon PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor CAR) and pregnane X receptor PXR), both heterodimerize with the ret- inoid X receptor RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds CAR) and dexam ethasone and rifampin-type of agents PXR). The peroxisome proliferator activated receptor PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fibrate-type of compounds leading to transcriptional activation of the promoters on CYP 4A gene. CYP7A was recognized as the first target gene of the liver X receptor LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor FXR) was identified as a bile acid recep tor, and its activation results in the inhibition of hepatic acid biosyn thes is and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these CYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RX R for CAR, PXR , PPAR , LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compo unds butylated hydroxyanisol BHA), tert-butylhydroquinone tBHQ), green tea polyphenol GTP), -)-epigallocatechin-3-gallate EG CG ) and the isothiocyanates PE ITC, sul- foraphane) generally appear to be electrophiles. They generally po ssess electrophilic-medi- ated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as hem e oxygenase-1 HO-1), with the subse quen t induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein P-gp), multidrug resistance-associ- ated proteins MRPs), and organic anion transporting polypeptide 2 OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, a nd play crucial roles in drug absorption, distribution, and excretion. Th e orphan nuclear receptors PX R and CAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the Correspondence to: A h-N g Tony Kong, Glaxo Professor of Pharmaceutics, Department of Pharmaceutics, Ernest Mario School of Phar- macy, Rutgers, The State University of N ew Jersey, 160 Frelinghuysen Road, Ro om 228, Piscataway, NJ 088 54, US A Tel: 732-445-3831 ext. 226 , Fax : 732-445-3134 E-mail: KongT @ ci.rutgers.edu 249
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I n d u c t io n o f P h a s e I II a n d III D r u g M e t a b o l is m / T r a n s p o r t b y
X e n o b i o t i c s
Changj iang Xu Chr is t ina Yong-Tao L i and Ah -Ng Tony Kong
Department of Pharmaceut ics, Ernest Mario School of Pharmacy,
P iscataway, NJ 08854, USARutgers, The State Univers i ty of New Jersey,
Received No vem ber 18, 2004)
Drug metabo l iz ing enzym es DME s) p lay cen tra l ro les in the metabo lism, e l imina t ion anddetox if ica t ion o f xenob io t ics and d rugs in t roduced in to the human body . Most o f the t issues
and o rgans in our body a re we l l equ ipped wi th d iverse and var ious DMEs inc lud ing phase I ,phase I I metabo l iz ing enzy me s and phase I II t ranspor te rs , wh ich a re p resen t in abund anceeither at the basal unstimulated level, and /or are inducib le at e levated level after expos ure toxenob io tics . Recent ly, ma ny impor tan t a dvanc es have been m ade in the mecha n isms tha t reg-u la te the express ion o f these d rug m etabo lism genes . Var ious nuc lear recep to rs inc lud ing thearyl hydrocarbon receptor AhR ), orphan nuc lear receptors, and nuclear factor-erythoroid 2p45-re la ted fac to r 2 Nr f2 ) have been shown to be the key med iato rs o f d rug- induced change sin phase I , phase I I metabol iz ing enzym es as we l l as ph ase I I I t ranspor te rs invo lved in e f f lux
mechan isms. For ins tance , the express ion o f CYP1 gene s can be induced by AhR , wh ichd imer izes wi th the Ah R nuc lear t rans loca to r Arn t ), in respon se to many po lycyc lic a rom at ichydrocarbon PAH s). Similar ly, the steroid family of orphan n uclear receptors, the constitut iveandros tan e recep to r CA R) and p regnane X recep to r PXR), bo th he te rod imer ize wi th the re t -ino id X recep to r RX R), a re show n to t ranscr ip t iona l ly ac t iva te the p romoters o f CYP 2B and
CY P3 A g e n e e x p re s s io n b y x e n o b io t i cs s u c h a s p h e n ob a rb i ta l -l ik e c o mp o u n d s CAR) a n d
dexam ethaso ne and r ifamp in -type o f agen ts PXR). The perox isom e pro l ife ra to r ac t iva tedrecepto r PPAR ), wh ich is one o f the fi rst charac te r ized me mb ers o f the nuc lear hormon erecepto r , a lso d imer izes wi th RXR and has been shown to be ac t iva ted by l ip id lower ing agentf ib ra te -type o f com poun ds lead ing to transcrip tiona l ac t iva t ion o f the p rom oters on CYP 4Agene. C YP 7A w as recogn ized as the f irs t ta rge t gene o f the l ive r X recep to r LXR), in wh ichthe e limina tion o f cho les te ro l depe nds on CY P7A . Farneso id X recep to r FXR ) was iden t if ied
as a b ile acid recep tor, and its act ivat ion results in the inhib it ion of hepatic acid b iosyn thes isand inc reased t ranspor t o f b i le ac ids f rom in tes t ina l lumen to the l ive r, and CY P7 A is one o f i tsta rge t genes . The t ranscrip tiona l ac t iva t ion by these recep to rs upon b ind ing to the p rom otersloca ted a t the 5 - f lanking reg ion o f these C YP genes genera lly leads to the induc t ion o f the i r
m RN A gene express ion . Th e phys io log ica l and the pharmaco log ical imp l ica t ions o f com mo npar tner o f RX R fo r CA R, PXR , PPAR , LXR and FXR recep to rs la rgely remain unknown and
are under in tense inves t iga t ions . For the phase I I DM Es, ph ase I I gene inducers such as thepheno l ic compo unds bu ty la ted hydroxyan iso l BHA), te rt -bu ty lhydroqu inone tBHQ), g reen teapolyphenol GTP ), -)-epigal locatechin-3-gallate EG CG ) and the isothiocyanates PE ITC , sul-
fo raphane) genera l ly appear to be e lec troph iles . The y genera l ly po ssess e lec t roph i lic -med i-ated stress response, result ing in the activat ion o f bZIP transcription factors N rf2 wh ichd ime r izes wi th Mafs and b inds to the an t iox idan t/e lec t roph i le respon se e lement AR E/E pRE )
promoter , wh ich is loca ted in many phase I I DMEs as we l l as many ce l lu la r de fens ive enzymessuch as hem e oxygenase-1 HO-1) , wi th the subse quen t induc t ion o f the express ion o f thesegenes. P hase III transporters, for exam ple, P-glycoprotein P-gp), mult idrug resistance-associ-a ted pro te ins MR Ps) , and o rgan ic an ion transport ing po lypeptide 2 OATP 2) a re expre ssed inm any t issu es such a s the l ive r, in test ine, k idney, and brain, a nd p lay crucia l ro les in drug
absorp tion , d is tr ibu t ion , and excre tion . Th e o rphan nuc lear recep to rs PX R and CA R have been
show n to be invo lved in the regu la tion o f these t ransporte rs. A long w i th ph ase I and ph ase I Ienzy me induc tion , p re t rea tment wi th severa l k inds o f inducers has been show n to a l te r the
Correspondence to: A h-N g Ton y Kong, Glax o Professor of P harmaceutics, Departm ent of P harmaceutics, Ernest Ma rio School of Pha r-macy, Rutgers, The State University of N ew Jersey, 160 Frel inghuysen Road, Ro om 22 8, Piscataway, NJ 088 54, US A
express ion of phase I I I t ransporters , and a l ter the excret ion o f xenobio t i cs , which impl ies thatphase I I I t ransporters may a lso be s im i lar l y regula ted in a coord inated fash ion, and prov idesan important mean to protect the body f rom xenobio t i cs insu l t s . I t appears that in genera l ,expo sure to phase I , pha se I I and ph ase I II gen e inducers m ay t r igge r ce llu lar s t ressresponse lead ing to the increase in the i r gene express ion, which u l t imate ly enhance the e l im i -nat ion and c learance of these xenobio t ics and /or o ther ce l lu lar s tresses inc lud ing harm fu l
react i ve in termediates such as react i ve oxygen spec ies (ROS), so that the body w i l l removethe s t ress expedi t ious ly . Consequent ly , th is homeostat ic re spo nse of the body p lays a cen-t ra l ro le in the protection o f the bod y against env i ronmenta l insu lt s such as those e l ic i ted b yexposure to xenobio t ics .
Key words: Phase I metabol i z ing enzyme s, Ph ase I I metabol i z ing enzyme s, P-Glycoprote in ,Mul t idrug resistance-associated protein, Organic anion t ransport ing polypept ide 2, Aryl hydro-carbon receptor , Pregnane X receptor , Const i tu t i ve androstane receptor , Perox isome pro l i fera-tor act i vated receptor , L iver X receptor , Farnesoid X receptor , Ret ino id X receptor , Nuc learfactor-erythoroid 2 p45-related factor 2
I N T R O D U C T I O N O F P H A S E I P H A S E II D R U G
M E T A B O L I Z IN G E N Z Y M E S A N D P H A S E III
D R U G T R A N S P O R T E R S
D r u g m e t a b o l i z i n g e n z y m e s ( D M E s ) p l a y c e n t r a l r o l e s
i n t he m e t abo l i sm , e l i m i na t i on and / o r de t ox i f i ca t i on o f
x e n o b i o ti c s o r e x o g e n o u s c o m p o u n d s i n t r o d u c e d i n to th e
b o d y ( M e y e r , 1 9 9 6 ) . I n g e n e r a l , D M E s p r o t e c t t h e b o d y
a g a i n s t t h e p o t e n t ia l h a r m f u l e x p o s u r e t o x e n o b i o t ic s f r o m
t h e e n v i r o n m e n t a s w e l l a s c e r t a in e n d o b i o t ic s . I n o r d e r t o
m i n i m i z e t h e p o t e n t ia l i n ju r y c a u s e d b y th e s e c o m p o u n d s ,
m o s t o f t h e t i s s u e s a n d o r g a n s a r e w e l l e q u i p p e d w i t h
d i v e r s e a n d v a r i o u s D M E s i n c l u d i n g p h a s e I , p h a s e I I
m e t a b o l i z i n g e n z y m e s a s w e l l a s p h a s e I I I t r a n s p o r t e r s ,w h i c h a r e p r e s e n t i n a b u n d a n c e e i t h e r a t t h e b a s a l
un i n duc ed l eve l , an d / o r i nduc i b l e a t e l eva t ed l eve l a f t e r
x e n o b i o ti c s e x p o s u r e ( M e y e r , 1 9 9 6 ; R u s h m o r e a n d K o n g ,
2 0 0 2 ; W a n g a n d L e C l u y s e , 2 0 0 3 ) .
P h a s e I D M E s c o n s i s t p r im a r i ly o f th e c y t o c h r o m e P 4 5 0
( C Y P ) s u p e r f a m i l y o f m i c r o s o m a l e n z y m e s , w h i c h a r e
f oun d ab un dan t l y in the l i ve r , gas t ro i n t es t i na l t rac t , l ung
and k i dney , cons i s t i ng o f f am i l i es and sub f am i l i es o f
e n z y m e s t h a t a r e c l a s s i f i e d b a s e d o n t h e i r a m i n o a c i d
s e q u e n c e i d e n t i t i e s o r s i m i l a r i t i e s ( G o n z a l e z a n d N e b e r t ,
1 9 9 0 ; G u e n g e r i c h , 2 0 0 3 ; M e y e r , 1 9 9 6 ; N e b e r t e t a L 1991 ;
N e l s o n e t a L 1 9 9 6 ) . M o r e t h a n t h i r t y - s i x g e n e f a m i l i e sh a v e b e e n d e s c r i b e d t o d a t e . T w e l v e f a m i l i e s e x i s t i n a l l
m a m m a l s , w h i c h c o m p r i s e t w e n t y - t w o s u b f a m i l i e s . I n
h u m a n , f i v e C Y P g e n e f a m i l i e s , s u c h a s C Y P 1 , C Y P 2 ,
C Y P 3 , C Y P 4 a n d C Y P 7 a r e b e l i e v e d t o p l a y c r u c i a l r o l e s
i n h e p a t i c a s w e l l a s e x t r a - h e p a t i c m e t a b o l i s m a n d
e l i m i n a t i o n o f x e n o b i o t i c s a n d d r u g s ( G o n z a l e z a n d
N e b e r t , 1 9 9 0 ; L e w i s , 2 0 0 3 ; N e b e r t e t a L 1 9 9 1 ; N e l s o n
e t a L 1 9 9 6 ; P a s c u s s i e t a L 2 0 0 3 b ; S i m p s o n , 1 9 9 7 ;
W a x m a n , 1 9 9 9 ) .
T h e p h a s e I I m e t a b o l i z i n g o r c o n j u g a t i n g e n z y m e s ,
c o n s i s t i n g o f m a n y s u p e r f a m i l y o f e n z y m e s i n c l u d i n g
s u l f o t r a n s f e r a s e s ( S U L T ) ( B a n o g l u , 2 0 0 0 ; W e i n s h i l b o u m
e t a l . 1 9 9 7 ) , a n d U D P - g l u c u r o n o s y l t r a n s f e r a s e s ( U G T )
( I nnocen t i e t a L 2 0 0 2 ; K i n g e t a L 2 0 0 0 ; M a c k e n z i e e t a L
1 9 9 7 ; T u k e y a n d S t r a s s b u r g , 2 0 0 0 ) , D T - d i a p h o r a s e o r
N A D ( P ) H : q u i n o n e o x i d o r e d u c t a s e ( N Q O ) o r N A D ( P ) H :
m e n a d i o n e r e d u c t a s e ( N M O ) ( J a i s w a l , 1 9 9 4 ; K o n g e t a L
2 0 0 1 a ) , e p o x i d e h y d r o l a s e s ( E P H ) ( G u e n t h n e r e t a l .
1989 ; H i nson an d Fo rke r t, 1995 ) , g l u t a t h i one S - t rans f e rase s
( G S T ) ( M o s c o w a n d D i x o n , 1 9 9 3 ; S c h i l te r e t a L 1 9 9 3 ;
T e w a n d R o n a i , 1 9 9 9 ) a n d N - a c e t y l t r a n s f e r a s e s ( N A T )
(Va t s i s e t a L 1 9 9 5 ) . E a c h s u p e r f a m i l y o f p h a s e I I D M E s
c o n s i s t s o f f a m i li e s a n d s u b f a m i l ie s o f g e n e s e n c o d i n g t h e
va r i ous i so f o rm s w i t h d i f f e ren t subs t ra t e spec i f i c i t y , t i ssue
a n d d e v e l o p m e n t a l e x p r e s s i o n , a s w e l l a s i n d u c i b i l i t y a n d
i n h i b i t o r y b y x e n o b i o t i c s ( H i n s o n a n d F o r k e r t , 1 9 9 5 ;Sch i l t e r e t a L 1993) . I n gene ra l , con j uga t i on w i t h phase I I
D M E s g e n e r a l l y in c r e a s e s h y d ro p h ili cit y, a n d t h e r e b y
e n h a n c e e x c r e t i o n i n t h e b i l e a n d / o r t h e u r i n e a n d c o n s e -
que n t l y a de t ox i f ica t i on e f f ect . A l t hou gh und er ce r t a i n
s i t u a t i o n s , c o n j u g a t i o n w i t h p h a s e I I e n z y m e s c o u l d r e s u l t
in a c t iv a t e d m e t a b o l i t e s a n d i n c r e a s e t o x i c it y ( C h e n e t a L
2 0 0 0 ; H i n s o n a n d F o r k e r t , 1 9 9 5 ; K o n g e t a L 2 0 0 0 ;
R u s h m o r e a n d K o n g , 2 0 0 2 ; S c h i l t e r e t a L 1993) . Fo r
e x a m p l e , r e a c t i v e e l e c t r o p h i l e s a r e t y p i c a l l y c o n j u g a t e d
w i t h g l u t a th i o n e ( G S H ) c a t a l y z e d b y v a r io u s G S T s , a n d
have been i m p l i ca t ed w i t h t he po t en t i a l o f f o rm i ng reac t i ve
i n t e r m e d i a t e s i n p a r t i c u l a r w h e n G S H l e v e l s i n t h e c e l l sa r e a t t e n u a t e d , c o n s e q u e n t l y r e s u l t i n g i n t o x i c o l o g i c a l
e f f e c t s ( B o l t o n a n d C h a n g , 2 0 0 1 ; B o l t o n e t a L 2 0 0 0 ) . O n
t h e o t h e r h a n d , t h e S U L T ( B a n o g l u , 2 0 0 0 ) a n d U G T
( S u g a t a n i e t a L 2 0 0 1 ; T u k e y a n d S t r a ss b u r g , 2 0 0 0 ) w h i c h
c a t a l y z e s u l fa t io n a n d g l u c u r o n i d a t i o n , m a y p l a y i m p o r t a n t
r o l e s i n t h e c o n j u g a t i o n a n d u l t i m a t e l y e x c r e t i o n a n d
e l i m i n a t i o n o f m a n y d r u g s a n d x e n o b i o t i c s c o n t a i n i n g
h y d r o x y l ( O H ) fu n c t i o n a l g r o u p e i t h e r p r e s e n t in t h e p a r e n t
s t r u c t u r e a n d / o r a f t e r b i o t r a n s f o r m a t i o n b y t h e p h a s e I
e n z y m e s s u c h a s t h e C Y P s ( B a n o g l u , 2 0 0 0 ; K i n g e t a L
2 0 0 0 ; S c h i l te r e t a L 1 9 9 3 ; S i m p s o n , 1 9 9 7 ) .
Phase I I I t ranspo r t e rs , i nc l ud i ng P -g l ycop ro t e i n (P -gp )
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Regulat ion o f Drug Metabol i sm and Drug Transport 253
W a n g a n d L e C l u y se , 2 0 0 3 ).
A l l P X R s ( h u m a n , m o u s e , r a t a n d s o o n ) a r e p r e d o m i -
n a n t l y e x p r e s s e d i n t h e l i v e r a n d i n t e s t i n e , a n d t o a l o w e r
l eve l i n t he k i dney and l ung . The t i ssue -spec i f i c d i s t r i bu -
t io n p a t t er n o f P X R s e x p r e s s i o n r e s e m b l e s t h a t of C Y P 3 A
( B e i g n e u x e t a L 2 0 0 2 ; C o u m o u l e t a l . 2 0 0 2 ) . T h e r e i sm o r e t h a n 9 5 % s e q u e n c e h o m o l o g y i n t h e D B D r e g i o n s ,
b u t o n l y 7 5 - 8 0 % a m i n o a c i d h o m o l o g y i n t h e L B D o f P X R
b e t w e e n t h e d i f f e r e n t s p e c i e s ( D u s s a u l t a n d F o r m a n ,
2 0 0 2 ; W a n g a n d L e C l u y se , 2 0 0 3 ) .
Const i tut ive androstane receptor CAR)
T h e o r p h a n n u c l e a r r e c e p t o r C A R ( N R 1 1 3) w a s id e n ti fie d
i n 1 9 9 4 ( B a e s e t a L 1994) . I t wa s o r i g i na l l y de f i ned as
cons t i t u t i ve l y ac t i va t ed recep t o r , be ca use i t f rom s a
h e t e r o d i m e r w i t h R X R w h i c h b i n d s t o r e t i n o i c a c i d
r e s p o n s e e l e m e n t s a n d t r a n s a c t i v a t e s t a r g e t g e n e s i n t h e
a b s e n c e o f l i g a n d s ( H o n k a k o s k i e t a L 1 9 9 8 b ) . C A R i s
m a i n l y e x p r e s s e d i n li v e r , a n d l e s s a b u n d a n c e i n t h e
i n te s t in e ( W a n g a n d L e C l u y s e , 2 0 0 3 ; W e i e t a L 2 0 0 2 ) . T w o
m e t a b o l i t e s o f a n d r o s t a n e , a n d r o s t a n o l a n d a n d r o s t e n o l
w e r e f o u n d t o b e th e e n d o g e n o u s C A R l ig a n d s . B o t h o f
t h e m a c t a s a n t a g o n i s t s b y d i s s o c i a t i n g C A R f r o m i t s
c o a c t i v a t o r a n d i n h i b i t i n g t h e t r a n s c a c t i v a t i o n o f C A R
i n s t e a d o f a c t iv a t in g C A R ( F r a s e r e t a L 2 0 0 3 ; G o o d w i n e t
a L 2 0 0 2 ; H o n k a k o s k i e t a L 2 0 0 3 ; P a s c u s s i e t a L 2 0 0 3 b ) .
C A R i s l o c a t e d i n t h e c y t o p l a s m o f h e p a t o c y t e s i n t h e
a b s e n c e o f l ig a n d s , a n d i t is tr a n s l o c a t e d i n to t h e n u c e l u s
a f t e r t r e a t m e n t w i t h p h e n o b a r b i t a l - l i k e C Y P 2 B i n d u c e r s .R e c e n t s t u d i e s i n d i c a t e d t h a t a c t i v a t i o n o f C A R i s a
m u l t i s t ep p rocess , t he i n i t i a l s t ep i s nuc l ea r t rans l oca t i on ,
w h i c h c a n b e i n d e p e n d e n t o f l i g a n d b i n d i n g , t h e f i n a l s t e p
i s C a M K - d e p e n d e n t a c t i v a t i o n o f t h i s r e c e p t o r ( B a e e t a L
2 0 0 4 ; M a g l i c h e t a L 2 0 0 2 ; P a q u e t e t a l . 2 0 0 0 ; W a n g a n d
L e C l u y s e , 2 0 0 3 ) .
Peroxisom e prol iferator act ivated receptors PPA R)
C u r r e n t ly , t h r e e m e m b e r s o f th i s n u c l e a r r e c e p t o r fa m i l y
h a v e b e e n i d e n ti fi e d a s : P P A R c ~ , P P A R ~ a n d P P A R T
( G e r v o i s e t a L 2 0 0 0 ; G i l d e e t a L 2 0 0 3 ) . P P A R ~ i s m a i n l y
exp res sed i n t he l i ve r , hea r t , k idney , i n t es t i ne and b row na d i p o s e t i s s u e . P P A R [ 3 i s w i d e l y e x p r e s s e d i n m o s t a d u l t
t is s u e s , a n d t h e b r a i n , k i d n e y a n d i n t e s ti n e a r e t h e h i g h e s t
e x p r e s s e d t is s u e s . P P A R T i s m a i n l y exs i t ed i n t he sp l ee n ,
i n te s t in e a n d f a t c e ll s , a n d i t i s c o m p o s e d o f tw o s u b m e m -
b e rs , n a m e d P P A R T 1 a n d P P A R ~ . P P A R s d e m o n s t r a t e d
d i s t i nc t bu t ove r l app i ng phys i o l og i ca l f unc t i ons (G i l de e t
aL 2 0 0 3 ; I s s e m a n n a n d G r e e n , 1 9 9 0 ; R u s h m o r e a n d
K o n g , 2 0 0 2 ; T u g w o o d e t a L 1 9 9 2 ; W a n g a n d L e C l u y s e ,
2 0 0 3 ) .
A t th e v e r y b e g i n n in g , P P A R ~ w a s f o u n d t o b e
ac t i va t ed by com pou nd s t ha t cau se p ro l if e ra t ion o f li ve r
pe rox i som es , hype rp l as i a and hepa t i c ca rc i nogenes i s i n
roden t s , however , subsequen t l y , s t ud i es sugges t ed t ha t
P P A R s m a y p l a y a c r u c i a l r o l e i n t h e r e g u l a t i o n o f
l ip o p r o t e in a n d f a t ty a c i d m e t a b o l i s m ( G e r v o i s e t a l . 2 0 0 0 ;
G i l de e t a L 2 0 0 3 ; S c h o o n j a n s e t a L 1 9 9 6 ; Y u e t a L
2 0 0 3 ) .
Liver X receptor LXR )
L i v e r X r e c e p t o r s a r e t r a n s c r i p t i o n f a c t o r s c o m m o n l y
k n o w n a s c h o l e s t e r o l s e n s o r s . T h e y a r e im p o r t a n t
r e g u l a t o r s o f t r a n s p o r t a n d m e t a b o l i s m o f s t e r o ls a n d f a t t y
a c i d s . T h e r e a r e t w o m e m b e r s o f th i s fa m ily , L X R o ~ a n d
L X R . L X R o ~ a n d L X R I3 s h a r e a h i g h d e g r e e o f a m i n o
a c i d s i m i l a r i t y ( - 8 0 % ) a n d a r e c o n s i d e r e d p a r a l o g u e s .
O x y s t e r o l s i n c l u d i n g 2 4 ( S ) , 2 5 - e p o x y c h o l e s t e r o l , 2 2 ( R ) -
h y d r o x y c h o l e s t e r o l , a n d 2 4 ( S ) - h y d r o x y c h o l e s t e r o l , a r e
n a t u r a l l i g a n d s o f L X R s . S o m e L X R - m e d i a t e d g e n e s
i n c l u d e t h o s e a s s o c i a t e d w i t h c h o l e s t e r o l a n d b i l e a c i d
m e t a b o l i s m a s w e l l a s t h o s e w i t h f a t t y a c i d s y n t h e s i s a n d
regu la t ion . LXRc~ i s p redo m i na n t l y e xp res sed i n li ve r , low er
l eve l i n k i dney , sp l een and i n t es t i ne . On t he con t ra ry ,
L X R I 3 i s l o c a t e d i n a l m o s t e v e r y t i s s u e t e s t e d . L X R s a r e
m a i n l y l o c a t e d i n t h e n u c l e u s , a n d m u s t h e t e r o d i m e r i z e
w i t h R X R f o r a c t i v a t i o n ( K h a n a n d V a n d e n H e u v e l , 2 0 0 3 ;
L e h m a n n e t a L 1 9 9 7 ; M e n k e e t a L 2 0 0 2 ; P e e t e t a L
1 9 9 8 ; V e n k a t e s w a r a n e t a L 2 0 0 0 ) .
Farnesoid X receptor FXR )
F X R w a s s h o w n t o b e a c t i v a t e d b y s u p r a p h y s i o l o g i c a l
c o n c e n t r a t i o n o f f a r n e s o l i n r a t s w h e n i t w a s o r i g i n a l l yi den t if ied . S i m i l a r to o t he r o rp han nu c l ea r recep t o rs , FXR
i s m a i n l y exp re ssed i n li ver and i n tes t ine , i t he t e rod i m er i zes
w i th R X R a n d b i n d s t o F X R r e s p o n s e e l e m e n t ( F X R E ) i n
t h e p r o m o t e r r e g i o n o f t a r g e t g e n e s . R e c e n t r e p o r t s
s h o w e d t h a t F X R w a s i d e n t i f i e d a s a b i l e a c i d r e c e p t o r ,
a n d w a s a c t i v a t e d b y p h y s i o l o g i c a l l i g a n d s r e s u l t e d i n t h e
i nh i b i t i on o f hepa t i c b i l e ac i d b i osys t hes i s and i nc reased
t ranpor t o f b i l e ac i d f rom t he i n t es t i ne t o t he l i ve r (de l
C a s t i l l o - O l i v a r e s a n d G i l , 2 0 0 0 ; M a k i s h i m a e t a / . 1999 ;
W a n g e t a / . 1 9 9 9 ; W a n g a n d L e C l u y s e , 2 0 0 3 ) .
Ret inoid X Rece ptor RXR )T h e r e a r e t h r e e m e m b e r s o f t h i s f am i ly , R X R c ~ , R X R
a n d R X R T . R X R ~ i s m a i n ly e x p r e s s e d i n t h e l i ve r , m u s c l e ,
k i d n e y a n d l u n g , a n d t o a l o w e r l ev e l i n t h e s p l e e n , h e a r t
a n d a d r e n a l g l a n d , w h e r e a s R X R ~ i s f o u n d i n a l l t i s s u e s
exce p t t he l i ve r and i n t es t ine , an d RX RT is f ound i n j us t a
f e w t i s s u e s , s u c h a s s k e l e t a l m u s c l e , h e a r t a n d c e n t r a l
n e r v o u s s y s t e m ( M a n g e l s d o r f e t a L 1 9 9 2 ; M a n g e l s d o r f
a n d E v a n s , 1 9 9 5 ; W a n g a n d L e C l u y s e , 2 0 0 3 ; Z e t t e r s t r o m
e t a L 1 9 9 6 ) . T h e m e t a b o l i t e 9 - c i s - r e t i n o i c ac i d o f v i t am i n
A w a s i n d e n t if a ie d a s a h i g h - a ff in i ty l ig a n d o f R X R s ( B a e s
e t a L 1 9 9 4 ) . R X R c a n f o r m h e t e r o d i m e r s w i t h o t h e r
o r p h a n n u c l e a r r e c e p t o r s a s a c o m m o n p a r t n e r , a n d t h e
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Nrfl, Nrf2, and small Maf proteins. A nuclear protein ARE-
BP1, has also been described to bind constitutively to the
ARE-inducible sequence, the GC box, and to be activated
by tBHQ possibly through a post-translational mechanism
(Itoh et aL 1997; Owuor and Kong, 2002), the exact
Fig. 2. A schematic representationof drugs/chemicals/xenobiotics nduces stress response eading o the potential sulfhydryl modification of Keapl-
Nrf2 and/or activation of the signaling pathways such as the non-receptor-mediated MAPK (ERK, JNK, and p38), PKC, PI3K and PERK. Theactivation of these signaling pathways eads to the activation of transcription factors such as Nrf2/Maf and increase in ARE-mediated gene
expression including he phase II DMEs (GST, NQO, UGT) as well as other cellular defensive enzymes (GCL, HO-1), which ultimately results n the
increase of detoxification of the xenobiotics and/or generated ROS, eading o a potential homeostaticcell survival response.
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