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Arch P harm Res Vo l 28, No 3 , 249-268, 20 05

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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

Tel: 732-445-3831 ext. 226 , Fax : 732-445-3134E-mail: KongT@ ci.rutgers.edu

249



250 C . Xu et a l .

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 )



Regulation of Drug Metabolism and Drug Transport 251

Brinkmann and Eichelbaum, 2001), mul t idrug resistance-

associated protein MRP ) Kerb e t a L 2001), and organic

anion t ransporting polypept ide 2 OAT P2) Ti rona and

Kim, 2002) are expressed in many t issues such as the

l iver, intest ine, k idn ey, and brain , wh ere the y p rovide a

formidable barr ier against drug penetrat ion, and playcrucial ro les in drug ab sorption, distribution, and excre tion

Brinkmann and E ichelbaum , 2001; Kim , 2003; Mizuno e t

aL 2003; Staudinger e t a L 2003). P -gp wa s f irs t reported

to be associated wi th mul t idrug resistance MD R) in

cancer chemotherapy. P-gp and MRP ut i l ize the energy

from the hydrolys is of ATP to substrate t ransport across

the ce l l mem brane, and are cal led AT P binding casset te

ABC) t ransporters Mizuno e t a l . 200 3). ABC transporters

belong to one of the largest superfami l ies of proteins, and

ei ther import or export a broad range of substrates that

inc lude amino acids, ions, sugars, l ip ids, xenobiotics, and

man y therapeut ic drugs Dean e t a L 2001; Kerb e t a L

2001). There are only exporters in the eukaryotes. In

hum an, 46 ABC transporters have been ident if ied Dean

e t a L 2001 ; Mizuno e t a L 2003). A l l ABC transporters a re

comp osed of two nucleot ide binding dom ains NBD s) and

two transmembrane domains TMDs) . The NBD is a lso

called an ABC, is the hal lmark feature of this tranporter

fami ly . The role of TMD is to recognize and med iate the

passage of substrates across the cel l mem branes Dean

e t a L 2001; Kerb e t a L 2001). A long wi th P-gp or MD R1;

ABCB1, the MDR subfamily inc ludes MD R3 ABCB4) ,

BSEP or SP-gp; ABCB 11) Br inkmann and Eichelbaum,2001) . The MRP subfami ly cons is ts o f MRP1 ABCC1) ,

MRP2 ABCC2) , MRP3 ABCC3) , MR P4 ABCC4) ,

MR P5 ABCC5) , MRP6 ABCC6) , MR P7 ABCC10) ,

MRP8 ABCC11) , and MRP9 ABCC12) Br inkmann and

Eichelbaum, 2001; Dean e t a L 2001; Kerb e t a L 2001;

Mizuno e t a L 2003) . M RP 1 and MR P3 are typica ll y

located on the basolateral membrane of polar ized cel ls ,

whereas MRP2 is general ly local ized to the apical

me mb rane cana licular in l iver), which im plies that in liver,

MRP2-mediated t ransport leads to increased excret ion

into bi le, but MRP1 - and MR P3-me diated t ransport into

blood leads to increased excret ion into the u r ine. Organicanion transport ing po lypept ide 2 OA TP 2; SLC21 A5) is a

member of the organic anion t ransport ing polypept ide

fami ly that mediates sodium- and ATP-independent

t ransport of a var iety of s t ructural ly unrelated endogen ous

and exogenous compounds, inc lud ing con jugated and

unconjugated bi l i rubin, conjugated steroids, neutral com-

pounds, some type I I organic cat ions, thyroid hormones

T3 and T4, and bi le salts Reichel e t a L 1999; Shi tara e t

aL 2002). OATP2 is local ized in the hepatic sinusoidal

mem brane, wi th select ive expression in the m idzonal to

per ivenous hepatocytes. P- gp , MR P and O ATP2 are al l

expressed on the brush-border m emb rane o f the intest inal

enterocytes, and excrete thei r substrates as wel l as

xenobiot ics/drugs into the lum en , resu l t ing in a potent ia l

l imi tat ion of net absorpt ion of drugs Dean e t a L 2001;

Kerb e t a L 2001; K im , 2003; M izuno e t a L 2003).

Therefore, the regulat ion of gene expression of var ious

phase I , phase I I DMEs and phase I I I t ransporters haspotent ia l impact on the metabol ism, el iminat ion, pharma-

cokinetics/dynamics, toxicokinetics/dynamics, drug-drug

interact ions of many therapeut ic agents, as wel l as thei r

abi l ity in the protect ion of the h um an body against exposure

of environmental xenobiot ics Guen gerich, 200 3; Rushmo re

and K ong, 2002; Wang and LeCluyse, 2003).

R E C E P T O R S I N V O L V E D I N T H E R E G U L A -

T I O N O F P H A S E I P H A S E II M E T A B O L I Z I N G

E N Z Y M E S A N D P H A S E I II T R A N S P O R T E R S

The human body has evolved versat i le inducible metab-

ol iz ing enzym es and ef f lux t ransporters to fac il itate the

metabol ism and e l iminat ion of potent ia lly ha rm ful drugs,

and/or xenobiot ics that are introduced f rom the envi roment.

The enzymat ic symtem inc ludes phase I enzymes, such

as CY P superfami ly Gueng erich, 2003; Lewis, 2003), as

wel l as phase I I enzymes, such as GST and UGT

Mackenzie e t a L 1997; Tew and Ro nai , 1999). The ef f lux

transporter system includes phase I I I ABC proteins, such

as P -gp, MRP2, and OA TP2 which remove the parent

drugs, metabol ites, and xenobiot ics f rom cel ls Dean e t

a L 2001; Lew is, 2003; Me yer , 1996 ; Mizuno e t a L 2003;Wang and LeCluyse, 2003). In order to understand the

regulat ion of gene expression o f phase I , phase I I metab-

ol iz ing enzyme s and p hase I II ef f lux t ransporters, one

would need to address the s ignal ing mechanism involv ing

the ary l hydrocarbon receptor AhR) Hahn, 2002; Rowlands

and Gustafsson, 1997), the orphan nuclear receptors

Moore e t a L 2000; Wang and LeCluyse, 2003) , and o ther

relevant t ranscr ipt ion factors and /or s igna l t ransduct ion

cascades Kumar and Thompson, 1 99 9; Wang and

LeCluyse, 2003) at the molecular level .

The AhR and orphan nuclear receptors comprise a

gene superfami ly encoding the t ranscr ipt ion factors thatsense endo genous, such as smal l l ipophi l ic hormon es,

and exogenous, such as drugs, xenobiot ics and t ransfer

into cellu lar responses by regulat ing the expression of

thei r target genes Levine and Perdew, 2001; Wan g and

LeCluyse, 2003). Regulat ion of gene expression at the

transcr ipt ional level by AhR and orpha n n uclear receptors

plays a crucia l role in the m etabol ism and c learance of

drugs and xenobiot ics that are introduced into the body

for the purpose of protect ion the body f rom the envi ron-

me ntal insults Li e t a L 1998; Rushmore and Kon g, 2002;

Wang and LeCluyse, 2003).



252 C. Xu et aL

Aryl hyd rocarbon receptorAhR is a m em ber o f the bas ic -he l ix - loop-he lix (bHLH ) -

Per-Arnt -S im (PAS) gene super family of t ranscr ipt ion

fac tor , and has been s tud ied fo r more than 30 years

(Hahn, 2002; Ro w land s and Gusta fsson, 1997) . AhR is

known to recognize a range of chemical s t ructures,inc lud ing non-aromat ic a nd non-ha logen ated com pou nds

(Elfer ink, 2003; H ahn, 2002; R ow land s and Gustafsson,

1997) . The AhR is highly polymorphic, especial ly when

compared w i th orphan nuc lear receptors , such as PXR

and C A R ( H onk ak os k i e t a L 2003; Wil lson and K l iewer ,

2002) . The bHLH mot i f exsists in many t ranscr ipt ion

factors su ch as M yc and M ax tha t f unct ions as seque nce-

speci f ic t ranscr iptional regulat ion. T his m ot i f p lays a role in

both DNA binding (basic region) and protein dimer izat ion

(HLH) (Hahn, 2002; Huang e t a l . 2004; K ikuchi e t a L

2003) .

The Ah receptor nuclear t ranslocator (Arnt ) , is not

required for nuc lear translocat ion pe r se, but is required to

genera te an AhR-Arn t complex w i th a greater a f f in i t y f o r

nuclear ext racts upon cel l d isrupt ion(Heid e t a L 2000;

Kikuchi e t a L 2003) . The un l iganded Ah R is f ound a lmos t

exclusively in the cytoplasm of the cel l , and t reatment with

l igand causes a t ime-dependent movement o f t he AhR

into the nucleus. The Arnt protein, on the other hand, is

found to be exclusively nuclear with or wi thout l igand.

Thus, l igand m ay serve to in i tiate translocat ion of the AhR

to the nuc leus whe re d imer iza t ion o f these tw o par tners

can occur . In Arnt -def ic ient cel ls , the AhR can st i l lt r ans locate to t he nuc leus in t he ce l l , a p rocess there fore

independent of Arnt (Hahn, 2002; K ikuchi e t a L 2003;

Levine and Perdew, 2001) .

AhR can b ind to DNA a s a heteromer ic complex . I t wa s

dem ons t r a t ed t ha t bo t h t he bH LH and P A S dom a ins a r e

required for DNA-binding, and thus presumably for d imer i-

zat ion with Arnt . The basic region of Arnt is not required

for dimer izat ion, but both hel ix regions, and ei ther the N-

terminal or C- terminal hal f of the PAS domain, are

essent ia l . The AhR and Arnt proteins have a s ingle

t ransact ive domain (TAD) in their C- terminals, compr is ing

am ino ac ids 521 - 640 i n t he A hR and am ino ac ids 582 -774 in A rn t (Huang e t a L 2004; K ikuchi e t a L 2003) .

The un l iganded AhR ex is t s in t he cy toso l complexed

with a dimer of Hsp90, which maintains the Ah R in a ligand-

binding conformat ion and prevents nuc lear t ranslocat ion

and/or dimer izat ion with Arnt (Heid e t a L 2000) . The

hydrophob ic AhR l igands enter t he ce l l by d i f f us ion and

are bound by the Hsp90-assoc ia ted AhR. L igand b ind ing

cau ses a conformat ional cha ng e resul ting in a receptor

spec ies w i th an inc reased a f f in i t y f o r DNA and a much

slow er rate of ligand dissociat ion. This event is ass ocia ted

w i th nuc lear trans locat ion and an exchan ge o f Hs p90 fo r

Arnt (Hahn, 2002; Heid e t a L 2000) . I t has been shown

that in a pur i f ied sys tem the AhR-Hsp90 complex is no t

dissociated by the addit ion of l igand. Ult im ately, the

recogn i t ion o f DRE enhancer sequences by the AhR-Arn t

com plex resul ts in the t ransact ivation of target gene s

(Hahn, 2002; Heid e t a L 2000; Lev ine and Perdew,

2001) .

Orphan nuclear receptorsOrpha n receptor is a subc lass o f nuc lear receptors tha t

binds to steroid-based l igands, suc h as cor t isol, est radiol ,

progesterone, aldosterone, tes tostero ne and v itamin D.

A l l t he known orphan receptors share two modu la tory

domains , one is t he h igh ly conse ved D NA-b ind ing dom ain

(DBD), the other is the l igand binding domain (LBD)

(Kumar and Thompson, 1999 ; Wang and LeC luyse, 2003) .

Th e D BD is character ized by two C 4- type z inc fingers,

l inks the receptor to the speci f ic promoter regions of i ts

ta rget genes , t e rmed hormone response e lement (HRE)

or xenob io t ic respon se e lement (XRE) . The DB D can

recogn ize the respo nse e lements tha t conta ins one or two

conse nsus core ha l f- s it es re la ted to the he xam er ACA AC A

(s tero id receptors ) o r AGG TC A (es trogen receptors and

so on) (Kumar and Thompson, 1999; Wang and LeC luyse,

2003) . D i f ferent orphan nuclear receptors bind to their

respon se e lement e i ther as hom odimers, as heterod imers

w i th the R XR, or as mono me rs . The L BD is loca ted in t he

carboxy- terminal por t ion of the r e ce p t o r and not on ly

s e r v e s as a docking s i te for l igands, but a lso contains

dimer izat ion m ot i fs : t ranscript ional act ivation doma ins,suc h as the act ivat ion funct ion 2 (AF-2) h el ix , and the

seq uen ce me diat ing the nu clear local izat ion of the receptor .

Ligand binding induces s igni f icant conformat ional changes

in the fo ld ing the LBD, and leads to the recrui tment of

coact ivator proteins and co-integrators, and trancact ivat ion

o f t he ta r ge t genes ( K um ar and Thom ps on , 1999 ; W ang

and LeCluyse, 2003) .

Pregnane X receptor PXR )PXR wa s f ir s t c loned f rom mo use l iver , t hen i ts homolo-

gou s counterpar ts in rat , rabbi t and hu ma n we re ident if ied

(Kliewer e t a / . 1998) . Or thologous receptors f rom di f ferentspec ies were g iven unre la ted names a t f i r s t due to the

lack o f a common nomenc la ture sys tem. The human

receptor of P• has also bee n referred to as steroid and

xenobiot ic receptor (SXR) or pregnane act ivated receptor

(PAR) ( • e t a / . 2000a, 2000b, 2001) . A nomenclature

sys tem has been dev ised fo r t he nuc lear receptor

supef family recent ly . Acc ording to th is system, P XR h as

been c lass fied a s N R l l2 . The gen e fami ly is des ignated

by an Arabic numeral , the supef family is indicated by a

capita l let ter , and indiv idual gene members are ident i f ied

by the second A rab ic numera l (Dussau l t and Forman,

2002; K l iewer e t a / . 1998 ; K um ar and Thom ps on , 1999 ;



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



254 C. Xu et aL

formation of a heterodimer with RXR is a critical step for

facilitating the specific binding and activation of all known

orphan nuclear receptors (Mangelsdorf and Evans, 1995;

Wang and LeCluyse, 2003; Zetterstrom et aL 1996).

There are two kinds of RXR heterodimers, nonpermissive

and permissive. RXR is completely silent and can only be

activated by the ligands of the partner orphan nuclear

receptor in the nonpermissive heterodimers. RXR permis-

sive heterodimers can be freely activated by ligands of

both RXR and partner nuclear receptors, such as PXR/

RXR, CAR/RXR, PPAR/RXR, LXR/RXR and FXR/RXR

(Mangelsdorf et aL 1992; Mangelsdorf and Evans, 1995;

Wang and LeCluyse, 2003; Zetterstrom et aL 1996).

Because RXRs have a broad binding ability with most

other orphan nuclear receptors, and affect the subsequent

regulation of their target genens, so the RXRs are involved

in the regulation of most drug metabolizing enzymes and

transport er directly or indirectly. But the untimate role of

RXR heterodimer complexs appear to be multifacedted

and yet uncertain (Rushmore and Kong, 2002; Wang and

LeCluyse, 2003).

REGUL TION OF PH SE I DMEs

It appears that in general xenobiotics exposure can

trigger certain stress respo nse to the body, and conse-

quently resulting in an increase in gene expression of

xenobiotic metabolizing enzymes or DMEs, so that the

body will be able to remove the stress insults as fast as

possible from the body (Fig. 1) (Kong et aL 2001a, 2001 b;

Rushmore and Kong, 2002).

The steroid family of the orphan receptors, PXR and

CAR can heterodimerize with the RXR, and have beenshown to transcriptionally induced CYP3A (Anakk et aL

2004; Coumoul et aL 2002; Lehmann et aL 1998) and

CYP2B (Bae et aL 2004; Beigneux et aL 2002) gene ex-

pression by xenobiotics such as dexamethasone/rifampin

type of compounds and phenobarbital-like compounds

(Bae et aL 2004; Coumoul et aL 2002; Honkakoski et aL

2003; Willson and Kliewer, 2002). PPAR is one of the very

first members to be identified in this orphan nuclear

receptor superfamily, and it can also heterodimerize with

RXR, that was initially found to be activated by the lipid

lowering agent fibrate-type of compounds and other

chemicals. Previously it was found to increase the levels

of peroxisomes in rodents, and later it was shown to

increase the gene expression of CYP4A enzymes (Gervois

et aL 2000; Rushmore and Kong, 2002; Simpson, 1997;

Zhou et aL 2002). LXR (Menke et aL 2002) and FXR

(Wolters et aL 2002) receptors are involved in the

regulation of CYP7A in mediating the elimination of

cholesterol and bosynthesis and excretion of hepatic bile

acids. These diverse array of naturally occurring or

synthetic compounds are primarily metabolized by CYP

Fig. 1. A schematic representationof drugs/chemicals/xenobiotics-induced tress response eading to the activation of specific receptor-mediated

gene expression of phase I drug metabolizing enzymes, the cytochrome p450s, phase II drug metabolizing enzymes, other stress enzymes, and

phase III transporters,which result n the enhancementof detoxification of the xenobiotics and a potential homeostaticcell survival response.



Regulat ion of Drug Metabol ism and Drug Transpor t 255

enz y m es i n t he body , and t hey r ange f rom endoge nous

com pou nds su ch as the s tero ids and cho les tero l t o d rugs

as w e l l as po tent ia l carc inogen s found in t he env ironment

( Lehm ann e t a L 1997 ; V enk a t es w ar an e t a L 2000; Wang

e t a L 1999) . The oxidized products are general ly more

polar , can be excreted direct ly and/or fur ther conjugatedby the phase I I DMEs and u l t imate ly e l im inated f rom the

body, and consequent ly detoxi f icat ion (Hinson and Forker t ,

1995; Meyer , 1996) . However , in some si tuat ions, notably

procarc inogens, they may be metabol ized to more react ive

species, and potent ia l ly promot ing toxic i ty and carc ino-

genic i ty (Banoglu, 2000; Guenger ich, 2003; Schi l ter e t a L

1993) .

Regula tion o f CY P by Ah R

W hen Ah R is bound by po lycyc l ic a romat ic hydrocarbo n

(PAH), such as dioxin and 3-methylchoranthrene (3-MC),

AhR t rans locates f rom the cy top lasm to the nuc leus ,

heterodimer izes with Arnt , and act ivates t ranscr ipt ion

through the XR E located in the prom oters o f CYP1 fami ly

genes (L i e t a L 1998; Nakaj ima e t a L 2003) . The

requ i rement o f AhR in CYP1 express ion induc t ion was

demonst ra ted in AhR-nu l l mutant m ice (Gonza lez and

Fernandez-Salguero, 1998; Shimizu e t a L 2000) . The ex-

press ion o f CYP1 gen es induced b y the AhR, in respo nse

to PAHs or ha logenated aromat ic hydrocarbon l igands

such as benzo[a]pyrene and 2,3,7,8- tet rachlorodibenzo-p-

dioxin (TCDD ) or dioxin is wel l establ ished (Gonzalez and

Fernandez-Salguero, 1998; Levine and Perdew, 2001; Lie t a L 1998; Nakaj ima e t a L 2003; Shimizu e t a L 2000) .

Regula t ion o f CY P 3A by P X R

Systemat ic delet ion analys is has dem ons t rated that

PXR response elem ent (PXR RE) is located in the promoter

reg ion o f CYP3A. The PXR response e lement is e i t her a

d i rec t repeat o f t he ha l f - s i t e TGAACT spaced by th ree

base pairs (DR3) or an ever ted or inver ted repeat of the

TGAACT ha l f - s i t e spaced by s ix base pa i r s (ER6 and

IR6) (Dussau l t and Forman, 2002; K l iewer e t a L 1998;

W a n g e t a L 2003; Wang and LeC luyse, 2003; X ie e t a L

2000b) . PXR can bind to and t ransact ivate these responseelements af ter act ivat ion by CYP3A inducers, and PXR is

the predominant regulator of the xenobiot ic- responsive

expression o f CYP 3A gen es (Anakk e t a L 2004; Coumoul

e t a L 2002; K l iewer e t a L 1998; X ie e t a L 2001) .

Th ere are impor tant species-speci f ic PX R activat ion

pro f i les to suppor t t he regu la t ion o f CYP3A by PXR. For

example , r i fampic in is a we l l - known and potent inducer o f

CY P3A in rabb it and hum an l iver , bu t no t in ra t and

mouse l i ver , and was found to be a potent ac t iva tor o f

human and rabb i t PXR, bu t no t o f ra t o r mouse PXR

( J ones e t a L 2000) . On the o ther hand, PCN is a po tent

ra t and mo use C YP 3A inducer, bu t no t o f human o r rabb it

CYP3A, and was found a lso to be a potent ra t PXR

act ivator , having very l i t t le ef fect on hu ma n an d rabbit

P X R ( J ones e t a L 2000; Staudinger e t a L 2001a, 2001b) .

Treatment of PXR-nul l mice with PCN fai led to induce

CYP3A express ion prov id ing def in i t i ve proof f o r PXR

regu la t ion o f CY P3A express ion (S taud inger e t a l . 2001 b;

X ie e t a L 2000a) . Replacem ent o f the mP XR with its

hum an or tho logue resu lted in t he xenob io tic respon se in

th is humanized mouse, a nd the resp onse to xenob io tic

st imulat ion resembled that in human (Anakk e t a L 2004;

Staudinger e t a L 2001b; X ie e t a L 2000a, 2001) .

Regula t ion o f CY P 2B by CAR

CYP2B is potent ly induced by phenobarbi ta l in most

mamm al ian spec ies . S tudy show ed tha t CAR can b ind to

a 5 1-base-pa i r m in imum sequ ence located in the 5 -

f lank ing reg ion o f t he CYP2B genes , and th is sequence

wa s requ i red fo r phenobarb ita l induct ion , and w as na me d

as phenoba rbi ta l- response element module (PBR EM )

(Honkakoski and Neg ish i, 1997) . PBREM is com pose d o f

two n uc lear receptor b ind ing s i t es (NR 1 and N R2) as we l l

as a nucle ar factor 1 (NF1) binding s i te. Both NR1 and

N R 2 a r e D R 4 m o t if s ( R am s den e t a L ~ 1999; Sueyoshi e t

a L 1999 ; Wang and LeC luyse, 2003). The h igh ly conserved

NR1 site is cr it ical for conferr ing phenobarbital responsive-

ness, the funct ion of NF1 s i te is st i l l unclear (Honkakoski

e t a L 1998b; Sueyoshi and Negishi , 2001) . Af ter t rans-

fec tion w i th som e kno wn nu c lear receptors , such as RXR,CAR, o r LXR, us ing PBR EM reporter assay to s tudy the i r

abi l i ty to bind and t ransact ivate the PBREM, only CAR

was found to be ab le to s t imu la te PBREM repor ter gene

expression (Honkakoski e t a l . 1998b) . Subsequent ly , NR1-

a f f in i t y choromatography was used to pur i f y t he pro te in

tha t bound to PBREM, and tha t bo th b ind ing assay and

Western b lo t assay demonst ra ted tha t CAR was the

protein that mediated the phenobarbi ta l induct ion response

(Honkakoski e t a L 1998b ; K aw am ot o e t a L 1999; Paquet

e t a L 2000; Sueyoshi e t a L 1999; Sueyoshi and Negishi ,

2001) .

Regula t ion o f CY P 4A by P P AR

PPAR is act ivated by a l igand- induced conformat ional

st ructure change, and binds to speci f ic upst ream region of

i ts target genes refer red to as peroxisome prol i ferator

r es pons e e lem en ts ( P P R E s ) ( Lam be and Tu gw ood ,

1996 ; Tugw ood e t a L 1996) . CY P4A cou ld be induced by

a number of peroxisome prol i ferators, such as c lof ibrate,

v ia the act ivat ion of PPARo~. CY P4 A plays a cent ral ro le in

the hydroxylat ion of fat ty acid der ivat ives and cholesterol

metabo l ism (Rushmore and Kong, 2002; S impson, 1997;

Y u e t a L 2003 ; Zhou e t a L 2002) .



256 C. Xu e t aL

R e g u l a t i o n o f C Y P 7 A b y L X R a n d F X R

LXR can recognize a direct repeat of two s imi lar

hexanucleot ide hal f -s i tes se para ted by 4 base pairs (DR4 )

in the upst ream regions of their target genes, refer red to

as an LX R E ( Lehm ann e t a L 1997; Wang and LeC luyse,

2003) . The en dogenou s oxysterols, such as the metabol i tes

of cholesterol , are select ive LXR l igands. The cholesterol

is metabol ized to hydrophi l ic b i le acids by CYP7A

(cholesterol 7~ -hydroxylase), and a cholesterol-r ich diet in

rat can upregulate CYP7A (Jet inek e t a L 1990; Je l inek

and Russe l l , 1990; Menke e t a L 2002; Peet e t a L 1998;

Wang and LeC luyse, 2003) . CYP7A was recogn ized as

the f i r s t t a rget gene o f LXR (Lehmann e t a L 1997) . The

DR4-LXRE is loca ted in t he prox imal p romoter reg ion o f

CYP 7A, and i t can b e spec if ica l ly boun d and ac t iva ted b y

L X R ( M e n k e e t a L 2002; Peet e t a L 1998) . LXRo~

knocko ut m ice are phenotyp ica l ly normal whe n fed w i th

low cholesterol d iet , but cholesterol accum ulat ion, chron ic

hepa tomega ly deve lopm ent an d l iver f unc tion impa i rment

occurred as compared to their w i ld- type counterpar ts

whe n the kn ock out m ice were fed w i th a h igh cho les tero l

d ie t (2%) , beca use the LXRo~ knocko ut m ice cou ld no t

regu la te the CYP7A gene express ion and the b i le ac id

b iosynthes is (Peet e t a L 1998 ). The LX R E o f C Y P 7A i s a

much s t ronger res pons e e lem ent f o r transcrip tion ac t iva-

t ion by LXRo~ han by LXRI3 . A l though LXR ~ express ion is

normal in LXRo~ knock out m ice , i ts p resen ce cou ld no t

prevent the cholesterol accumulat ion and l iver funct ion

d isorder when these mice wer9 fed w i th h igh cho les tero ld ie t (Lehmann e t a L 1997 ; V enk a t es w ar an e t a L 2000;

Wang and LeC luyse, 2003) .

The binding and act ivat ion of FXR by bi le acids

accum ulat ion wa s fol lowd by the t ranscr iptional act ivation

of i leal b i le acid-binding protein ( IBABP), that resul ted in

the increase of b i le acid reabsorpt ion (Makishima e t a L

1999; Wang and LeC luyse, 2003) . FXR can negat ive ly

regu la te CYP7A express ion by b ind ing to i t s b i le ac id

l igands , bu t un t i ll now there is no ev idence show ing tha t

FXR can b ind d irec tly to t he C YP7 A promoter reg ion . FXR

is the main regulator in facil i tat ing bile acid reabsorpt ion

( IBABP act ivat ion) and i t is an inhibi tor of CYP7A(cholesterol hyd roxylase) (del Cast i l lo-Ol ivares and G i l ,

2000; Denson e t a L 2001; Wan g and LeC luyse, 2003) .

C r o s s t a lk a m o n g t h e o r p h a n n u c l e a r r e c e p to r s

The ind iv idua l respo nse e lements o f t he d if fe rent pha se

I CYP genes can be ac t iva ted by more than one s ing le

nuc lear receptor , and i t is com m only referred to as cross-

ta lk . R ecent s tudy found tha t PX R can b ind to the

PBREM located in t he 5 ' - f lank ing reg ion o f t he CYP2B

(Pascussi e t a L 2003b; Sueyosh i and Neg ish i , 2001;

Wang and LeC luyse, 2003) . Dexamethasone is a l igand

for mo use P XR bu t no t an ac tiva tor f o r mou se CAR, s tud y

revealed that i t could potent ly induce CYP2B10 expres-

s ion in mouse hepatocy tes (Wang and LeC luyse, 2003;

Wei e t a L 2002) . PXR act ivators such as r i fampin,

phenob arbi ta l , phenytoin and c lot r imazo le (an PXR act ivator

but CAR deac t iva tor ) can e f f ic ien t ly induce CYP2B6 ex-

press ion in human hepatocy tes (Honkak osk i e t a L 1998a,1998b; X ie e t a L 2000b) . A l l PXR ac t iva tors can t rans-

ac t iva te CY P2B 6 hPB REM repor ter gen e express ion a fte r

co t rans fec t ion o f hPXR w i th the CYP2B6 hPBREM or

NR1 repor ter vectors in huaman hepatocytes. A distal

xenob io tic respons ive e nha ncer modu le (XREM ) wa s

found to be located in t he prom oter o f t he C Y P 2 B 6 g e n e

recently , and both P XR a nd C AR can b ind to and ac t iva te

th is nove l XREM (Wang e t a l . 2003) . Transfect ion of both

PBREM and XREM was found to max imal ly ac t iva te

CYP2B6 repor ter gene (Wang e t a L 2003 ; W ang and

LeCluyse, 2003) . A l l these resul ts st rongly suppor t the

not ion that PXR plays an impor tant ro le in the regulat ion

of C Y P 2 B gene . B o t h C Y P 2C 8 and C Y P 2C 9 ex p r es s ion

can be induced by PXR ac t iva tors such as r i f ampin , SR-

12813 and pac l i t axe l in human hepatocy tes , sugges t ing

t ha t a P X R r es pons e e lem en t m ay be p r es en t i n t he

promoter reg ion o f t hese genes (Pascuss i e t a L 2003b;

W a n g e t a L 2003) . To date , severa l DR4 and DR5

elements have been found in the upst ream 5' - f lanking

region of CYP2C9 star t s i te. The role of PXR in the

transcript ional regulat ion of C Y P 2 C gene express ion is

st il l unclear , and n eed s futher invest igat ion of the upst ream

region of the C Y P 2 C gene promoters (Ferguson e t a L2002; Pascuss i e t a L 2003b; Wang and LeC luyse, 2003) .

CYP7A was a lso repor ted to be regu la ted by PXR

(Staudinger e t a L 2001a, 2001b; Wang and LeC luyse,

2003; Waxman, 1999) .

A l though C AR a nd PXR we re or ig ina lly identi fied as the

regu la tors o f CYP2B and CYP3A, respec t ive ly , t here are

a lot of cross- talk between the induct ion of these target

gene s by thes e two com pound s . Th is is due in par t t o the

fac t t ha t bo th CAR and PXR can recongn ize o ther

response e lements such as DR3, DR4 or ER6, and

resu lt ing in the induc t ion o f CYP 3A and C YP2 B b y e i ther

common or se lec t ive l igands . Both CAR and PXR canregu la te the CYP3 A and CY P2B gen e express ion by the i r

speci f ic l igands in CV-1 cel ls a s wel l as in hepatocytes

(Wang e t a L 2003; Wang and LeC luyse, 2003; X ie e t a L

2000b, 2001 ).

UGT s play an impor tant ro le in phas e I I metabol ism, and

they are mainly expressed in the l iver . Phenobarbi ta l has

been used for the t reatment of Cr ig ler -Naj jar syndrome for

qu i te some t ime, and i t was repor ted to induce UGT1A1

(Innocent i e t a L 2002; Sugatani e t a L 2001) . UG T1A 1 is

the speci f ic isozyme responsible for b i l i rubin conjugat ion

and detox if ica t ion . A 29 0-base -pa i r d is ta l enhan cer

containing three p utat ive nuclear receptor mo t ifs was fou nd



Regulation of Drug Metabolism and Drug Transport 257

and identified to be necessary for UGT1A1 induction by

phenobarbital, and it was considered to be correlated with

the regulation by CAR (Pascussi et aL 2003a; Ritter et aL

1999; Sugatani et aL 2001; Wang and LeCluyse, 2003).

Overall, the transcriptional regulation of phase I drug

metabolizing enzymes is a multifaceted and complicatedprocess. A single orphan nuclear receptor may mediate

the induction of multiple targe t genes, and conversely, a

single gene may be coregulated by multiple orphan

nuclear receptors and ligands.

REGUL TION OF PH SE II DMEs

The role of phase II conjugation in the metabolism of

drugs and xenobiotics in the human body has been

studied for a long time however, the mechanism of phase

II gene s regulation remains unclear until recently. Many

structurally unrelated chemicals including the PAHs,

barbiturates and many naturally occurring cancer

chemopreventive agents including phenolic antioxidants,

isothiocyanates and flavonoids were all found to induce

phase II genes (Chen et aL 2000; Hu et aL 2004; Keum

et aL 2003; Owuor and Kong, 2002; Schilter et aL 1993;

Shen et aL 2004). Further studies of the promoters of

some of the phase II genes revealed the existence of

several cis-acting regulatory elements, such as the anti-

oxidant response element (ARE)/electrophile response

eiement (EpRE), xenobiotic-responsive element (XRE)/

aromatic hydrocarbon responsive element (AhRE), activator

protein-1 (AP-1), and nuclear factor -kappa B (NF-~B)binding sites in their 5 -flanking regula tory region (Hu et

aL 2004; Itoh et aL 1997; Keum et aL 2003; Kong et aL

2001a; Rushmore and Kong, 2002; Shen et aL 2004).

Most recent findings suggest and support the key role of

the ARE/EpR E in the regulation of expression of some

phase II genes such as NQO, GST, and UGT by phenolic

antioxidants and other naturally occurring cancer chemo-

preventive agents (Chen et aL 2000; Hu et aL 2004;

Keum et aL 2003; Kong et aL 2001a, 2001b; Owuor and

Kong, 2002; Rushmore and Kong, 2002; Shen et aL

2004). Recently, several ARE/EpRE-binding proteins have

been proposed and identified, including the members of

basic leucine zipper transcription factor (bZIP) family,

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.



258 C. Xu e t aL

identi ty of this protein is sti l l unclear, presumably could be

related to N rf2/Maf complex. Th e central role of Nrf2 in the

transcr ipt ional act ivation of ARE-reporter genes has been

conf i rmed recent ly in other ARE-m ediated gen es inc luding

hum an ~-glutamylcysteine l igase GC L), and mo use hem e

oxygenase-1 HO-1) Chen e t a l . 2000; Kong e t a l . 2000,2001 a , 2001 b ; Ow uor and Kong, 2002; Shen e t a l . 2004).

The induct ion of NQ O and GS T by the phenol ic ant iox idant

BHA wa s largely el iminated in the intest ine and l iver of

Nrf2-/- m ice, and the gene expression o f several detoxi-

f icat ion enzymes inc luding NQO was markedly reduced in

the lung of Nrf2 - / - mice I toh e t a L 199 7) . Th is lack o f

phase I I DM E induct ion in Nrf2 - / - mice strongly suggests

that Nrf2 is the most l ikely transcriptional factor involved in

the transcription activation of ARE-mediated phase II

genes and cel lu lar defense genes induct ion Chan and

Kan, 199 9; I toh e t a L 1997 ; K w ak e t a L 2001).

Qust ions remain over the past few years as to how N rf2

is transcriptionally activated by such diverse chemical

compounds. Several models have been proposed and put

forward as dep icted in Fig. 2 and the biolog ical real ity

probably inv olve the convergent of some or al l of these

mul t ip le s ignal ing pathways depending on the chemical

structures, cel l or t issues types, the gene of interest and in

conjuct ion wi th other s ignal ing events that are yet to be

uncovered.

Previously, our group has shown that the mi togen-

act ivated protein k inase MAP Ks) are involved in the

regulat ion of the ARE in a Nrf2-dependent manner usingtransient transfection studies as well as kinase specif ic

chemical inhibitors Yu e t a L 2000a). We found that the

extracellu lar s ignal -regulated k inase 2 and 5 ERK2 ,

ERK5 ), and c-Ju n N-terminal k inase 1 JN K1) upregulated

the A R E K eum e t a L 2003; Shen e t a L 2004; Yu e t a L

1999), whi le the p38 M AP K appears to suppress i t Yu e t

a L 2000b).

Th e phosphat idy l inosi to l 3-k inase PI3K) has been

postulated to be a posi t ive regulator of ARE in IMR-32

neuroblastoma by the use of PI3K chemical inhibi tor,

wortmannin Lee e t a l . 2001). Kang e t a l . provided further

evidence that PI3K may be involved in Nrf2 nucleart ranslocat ion in response to tBH Q-induced oxidat ive stress

in conjunct ion wi th cytoplasmic act in rearrangement Kang

e t a L 2002). Furthermore, Huang e t a L have reported that

protein k inase C PKC) can di rect ly phosphorylated N rf2

Huang e t a L 2000) and Ser-40 appears to be a s i te of

potent ia l phosphorylat ion Hu ang e t a l . 2002). Furthermore,

Cull inan e t a L have indicated that Nrf2 is directly

phosphorylated b y PERK, a t ransmem brane t ranscr ipt ion

factor, fol lowing the accumulation of unfolded proteins in

the endoplasmic ret iculum ER) Cul l inan and Diehl , 2004;

Cull inan e t a L 2003). Ta ken together, these resul ts suggest

that mult iple kinase pathways are involved in the tran-

scriptional activation of ARE.

The most compel ing regulatory mechanism of act ivat ion

of Nrf2 other than phosphorylat ion, have been reported

recent ly . Dinkova-Kostova e t a L have shown that phase I I

inducers, most of wh ich are strong electrophi les, can resul t

in di rect c leavage of Nrf2-Keapl comp lex by modi fy ingKe ap l at cysteine residues through Michael react ion

Dinkova-Kostova, 2001, 2002a, 2002b). To support th is

hypothesis, Wakabayashi e t a L recent ly show n that two of

the 15 cysteine residues Cys273 and Cys288) in Ke ap l

may play an important ro le in releasing Nrf2 in response

to electrophiles and oxidative stress via the formation of

an intermolecular disulf ide bridge, at least in the test tube

Wakabayashi e t a L 2004). Quest ions remain whether

this wil l occur in cel ls or i n v i v o t issues. In addi t ion, the

presence o f an ARE-l ike sequence in the promo ter region

of Nrf2 have also been shown, which may be responsible

for sustaining the durat ion of ARE act ivat ion by providing

the binding s i te of Nrf2 i tsel f , as a feedb ack control

mechanism Kwak e t a L 2002). Interestingly, strong

phase II inducers such as cadm ium, tert -buty lhydroquinone

tBHQ), and beta-naphthof lavone ~-NF) did not af fect

Nrf2 mR NA level in certain ce l l types, but a t tenuated

ubiqui t inat ion and proteosomal degradat ion of Nrf2,

imply ing that the act iv i ty of Nrf2 may not be determined

transciptionally but perhaps post-translationally, at least in

these cells types Alam e t a L 2003; Nguyen e t a L 2003;

Stewart e t a L 2003). F uture studies in i n v i v o animal or in

human into the activation of these mult iple signalingpathways by xenobiot ics wi l l y ie ld bet ter ins ights into

mechanisms of act ivat ion of Nrf2 leading to the induct ion

of phase I I drug m etabol iz ing enzym es as wel l as cellu lar

defensive enzymes and thei r b iological consequences in

the protection against environmental insults.

R E G U L T I O N O F P H S E III T R N S P O R T E R S

The major determinants of the i n v i v o systemic bioavail-

abi l i ty of many drugs are due in part to the physico-

chem ical properties solubi l i ty, ionization, l ipop hil ity), intes-

t inal absorpt ion/permeabi l i ty and the intest inal/hepat icf irs t -pass e f fect . The P-glycoprotein P-gp) or mul t idrug

resistant MD R) protein is usual ly coexpressed and co-

induced wi th C YP 3A in the l iver and intest ine. I t p lays an

important role in reducing drug ab sorpt ion and enha ncing

drug el iminat ion back to the gut lum en, and i t appers that

i t m ay be regulated by PXR Johnson e t a L 2003; Per lof f

e t a L 2004). P-gp is expressed at the ap ical surface of

the intest inal enterocytes, whe re i t mediates the e f f lux of

xenobiot ics into the intest inal lumen before these com-

pounds can access the po rtal and subsequen t systemic

ci rculat ion. PXR l igands such as r i fampic in, SR-12813,

51~-pregn ane-3-20-dione, clotrimazole, m ifepristone and



Regulation of Drug Metabol ism and Drug Transpor t 259

n i fed ip ine have been demonst ra ted to induce M D R 1 in

hepatocy te and co lon cancer ce l l l ines (LS180 and

LS174T) (Kul lak-Ubl ick and Becker , 2003; Song e t a L

2004; Wang and LeCluyse, 2003) . Const i tut ively act ivated

hPXR expressed in LS180 ce l ls was ab le to induce both

P-gp and C YP 3A expression without speci f ic ligand binding.I t appe ars tha t a s im i lar P XR -depen dent mechan ism may

be also involved in M D R 1 induc t ion as compared to

C Y P 3A induc t i on . E ndogenous M D R 1 gene is highly

inducible by r i fampin in human colon carc inoma cel l l ine

LS174T, using DNA binding and t ransfect ions assays. A

DR4 nuc lear receptor response e lement in t he ups t ream

enhancer a t about 28 k i lobase pa i r s was ident i f ied as a

dist inct PXR binding s i te that was essent ia l for M D R 1

induct ion by r i fampin (Geick e t a L 2001) .

Most rece nt ly , ma ny s tud ies have d em onst ra ted tha t

PXR act ivat ion resul ts in the induct ion of several other

t ranspor ters inc luding OATP2 (Staudinger e t aL 2001a,

2001b) , MRP2 or canal icular mult ispeci f ic organic anion

t ranspor ter (cM OAT ) (Kast e t aL 2002) , and M RP3 (Ku llak -

Ubl ick e t aL 2004; Teng e t aL 2003) . MRP2 is main ly

exp ress ed in l iver, intestine, and k idne y tubules, S imi lar to

Pgp, MR P2 is loca lized to the ap ica l me mb ranes o f t hese

t issues (Chan e t a L 2004) . M RP2 is o r ig ina lly des ignated

as the cMOAT, is responsible for the bi l iary excret ion of

organic anions inc luding leukot r iene C4 (LTC4) , d ivalent

bi le sal ts , and phase I I g lutathione, glucuronide, and sul-

fate conjugates. Absence of th is t ranspor ter in hepato-

cytes is bel ieved to be the reason for the defect in bi l iaryexcret ion of organic anions in pat ients with Dubin-Johnson

syndrome (Kon ig e t a L 1999a, 1999b) . I t appears that the

s ubs t r a t es o f M R P 2 and P gp t o s om e deg r ee a r e

over lapping. The co- local izat ion of MRP2 and PgP at the

apical membrane may be impor tant in drug disposi t ion,

and may present a formidable barr ier to the absorpt ion of

m any d r ugs ( C han e t aL 2004) . Co-expression of MRP2

wi th re levant phase I I metabo liz ing e nzym es su ch as GS T

and UG T, wh ich are found to be ex pressed notab ly a t

s i tes w he r e C Y P 3A 4 , P gp and M R P a r e found i nc lud ing

the l iver , intest ine an d k idney, i t is possible that MR P2 a nd

GST, UGT may play a synergist ic ro le in mediat ing drugel iminat ion (Chan e t aL 2004; Co les e t a L 2002; Turgeon

e t aL 2001 ). FX R , P X R and C A R appe a r t o be

respons ib le fo r induc t ion o f Mrp2/MRP2 mRNA in ra t ,

mouse and human hepatocy tes (Kas t e t a l . 2002) . Kast

e t aL f ound tha t MRP2 mRNA leve ls were induced

fo llow ing t rea tment o f hum an or ra t hepa tocy tes w i th FX R

l igands and P X R o r C A R agon is ts . The dex am e t has one -

and pregnenolone 16o~-carbonit r i le-dependent induct ion

of MRP2 express ion was not ev ident in hepatocy tes

der ived f rom PXR nul l mice. In cont rast , induct ion of

MRP2 by phenobarbi ta l , an act ivator of CAR, was

comparable in wi ld- type and PXR nul l mice. An unusual

26-bp sequence was ident i f ied 440 bp ups t ream of t he

MRP2 t ranscr ipt ion in i t iat ion s i te that contains an ever ted

repeat o f t he AG- I -FCA hexad se para ted by 8 nuc leo tides

(ER-8) . PXR, CAR, and FXR bound with high af f in i ty to

this element as heterodimers with the RXR. Fur thermore,

the iso la ted E R-8 e leme nt was capa b le o f conferr ing PXR,CAR, and FXR responsiveness with the heterologous

thymidine k inase (TK) promoter . Mutat ion of the ER-8

element abol ished the nuclear receptor response. These

s tud ies demonst ra te tha t MRP2 may be regu la ted by

three dist inct nuc lear receptor s ignal ing pa thw ays that

c onv e r ge on a c om m on r es pons e e lem en t i n t he 5 -

f lanking region of th is gene (Kast e t a L 2002) .

M RP 3 is a basolateral e f flux t rans por ter that t ranspo r ts

bi le acids as wel l as several c l in ical ly impor tant anionic

drugs such as etoposide, methot rexate, and glucuronide

con jugates . The express ion o f MRP3 in ra t and human

l iver is low under normal condit ions but is induced dur ing

cho les tasis and in the a bsen ce o f M RP2 or b i le sa l t export

pump. Up- regu la t ion o f t h is t ranspor ter appears to

compensate for the diminished abi l i ty to excrete organic

anions into bile. For example, M RP 3 expresson is increased

in pa t ien ts w i th Dub in-Johnson syndrome to compensate

for a def ic iency in bi liary excret ion of organic an ions (Konig

e t a L 1999a, 1999b) . E levated expression of MRP3 is

also observed in the natural ly occurr ing MRP2-di f ic ient

eisai hyperbil irubinemic rats (Hirohashi e t a L 1998) .

MRP3 is also bel ieved to play an impor tant ro le in the

enterohepat ic c irculat ion of b i les sal ts (C ha ndra andBrouwer , 2004) . PX R is also act ivated by bi le acids, which

l ikely to prevent their accumulat ion to tox ic levels

(Staudinger e t a L 2001b; X ie e t a L 2001) . When the

human hepatoma ce l l lines HuH7 and H epG 2 were t rea ted

with PX R act ivators inc luding c lot r imazo le, r i fampic in,

1713-hydroxy-11J3-[4-dimethylaminophenyl]-17(z-[1 propynyl]

es t ra -4 ,9-d ien-3-one (RU486) , mety rapone, n i f ed ip ine ,

l i t hocho l ic ac id , and PCN, the leve ls o f MRP3 mRNA

we re induced 1 .6- t o 8-fo ld in a dose -depe nde nt manner .

Cor respond ing decreases in t he mul t id rug res is tance-

ass ociated pro tein-de pen den t cel lu lar retent ion of 5-

carboxy f luoresce in we re a lso seen in the t rea ted H uH7ce l ls . I n v ivo s tud ies demo nst ra ted inc reased PXR mR NA

and induc t ion o f MRP3 mRNA in the l i vers o f w i ld - t ype

mice t reated with the PXR act ivator RU486. On the other

hand, M RP3 induc tion wa s not seen in t he RU 486- t rea ted

PXR-nul l m ice. Th ese resul ts sugg est that PX R act ivat ion

may play an impor tant ro le in the regulat ion of MRP3

express ion (Teng e t a L 2003) . Delet ion analys is of the

Mrp3 p romo ter ident if ied a basa l transcr ip t ion e lem ent a t

-123/ -106, two negat ive response regions at -2723/ -1128

and -530/ -443, respect ively, as w el l as two posi t ive response

reg ions a t -1063/ -943 and-302/ -157. S i te -d i rec ted muta-

genes is ana lys is and ge l mob i l i t y sh i f t assays prov ided



260 C. Xu et aL

evidence for Spl and Sp3 binding wi thin the -123/-105

regions. These studies indicated that Spl and Sp3 may

be involved in the regulat ion of the rat Mrp3 gene (Tzeng

and H uang , 2002 ) . B o th MR P 3 mR N A l eve l and t he

promoter act iv i ty of MRP3 were increased about 3-fold in

hum an colon cel ls by the bi le acid cheno deoxychol ic a cid(CDCA ), and that the putat ive bi le sal t- responsive elements

we re found to be located in the reg ion -229/-138, which

include tw o alpha-1 fetoprotein t ranscr ipt ion factor (FTF )-

l ike elements. C onstruct of a spe ci fic m utat ion in the con-

sensus sequence of FTF eleme nts shewed no increase in

the basa l transcr iptional act iv i ty fo l lowing CDC A treatment.

In electrophoretic mobil i ty shift assay with nuclear extracts,

speci f ic binding of FTF to FTF-i ike eleme nts was obse rved

when t reated w i th CDCA. The express ion o f FTF mRNA

levels was also markedly elevated af ter t reatment wi th

CDCA, and overexpression of FTF speci f ical ly act ivated

the M RP 3 promoter a ct iv i ty about 4-fo ld over the basal

promoter act iv i ty . These resul ts suggest that FTF may

play an important role in the regulat ion of M RP3 expression

(Inokuchi et a l . 2001).

Select ive act ivat ion of PXR or CAR induced OATP2

and MRP3 expression in wi ld- type mice but not in PXR

knock out (PXR-KO) mice (Staudinger et a l . 2003).

Treatment of wi ld- type mice wi th the PXR-seiect ive

act ivator PCN resul ted in robust increases in Oatp2,

Mrp3, and CYP3A gene expression levels. Treatment of

wi ld- type mice wi th the CAR act ivator phenobarbi tal

induced only s l ight increases in Oatp2, Mrp3, and CYP3Agene expression levels. In contrast to t reatment wi th ph e-

nobarbi ta l , t reatmen t of wi ld-type mice wi th the CAR -selec-

t ive activator 1,4-bis[2-(3,5-dichlorophyridyloxy)]benzene

(TCPOBOP) potent ly induced increases in Oatp2, Mrp3,

and CY P3A gene expression leve ls . There we re no

changes in Oatp2, Mrp3, and CYP3A gene expression

whe n PXR -KO mice were treated w i th P CN , however ,

phenobarbi tal t reatment of PXR-KO mice produced

relat ively obvious increases in Oatp2, Mrp3, and CYP3A

gene expression when compared wi th the phenobarbi tal -

t reated w i ld-type mice (Staudinger e t a L 200 3), suggest ing

the importance of CAR and PXR in the co-regulat ion ofthese t ransporters. In the same study , MR P2 e xpression

was s igni f icant ly induced by phenobarbi tal and this was

simi lar ly reported in rat l iver that M RP2 (cMOA T) was

found to be induced by phenobarbi tal us ing microarray

gene chip study (Rushm ore and K ong , 2002).

OAT P2 is localized to the h epat ic s inusoidal m emb rane,

wi th select ive expression in the m idzonal to per ivenous

hepatocytes (Reichel et a l . 1999 ) . Expression o f O ATP2

has also been detected in the brain and ret ina (Gao e t a L

2002). Treatment of ra ts wi th PX R act ivator P CN , s ignif i-

cant ly enhances the rat o a t p 2 gene expression (Guo e t

a L 200 2a, 200 2b). Four potent ia l PXR respo nse elements

(PXREs) we re ident i fied in the 5 - f lanking region of the rat

oatp2 gene. One element (DR 3-1) is located approximately

-5000 bp w i th th ree more (DR3-2, DR3-3, and DR3-4)

c lustered at about -8000 bp. Resul ts f rom electrophoret ic

mobi l i ty shi f t assays sh ow ed that the PXR -RXR heterodi -

mer binds to the DR3-2 wi th the highest af f in i ty , to theDR3-4 and DR3-1 wi th a lower af f in i ty , and weakly or not

at al l to the D R 3-3 . Furthermore, a ser ies of part ia l

deletions o f the 5 -f lanking reg ion i l lustrated that both the

proximal and d istal c lusters of P XREs are requ ired for

maximal induct ion of rat OATP2 by PCN (Guo et a l .

2002a, 2002b).

C O O R D I N A T E D R E G U L A T I O N O F P H A S E I

P H A S E II D M E S A N D P H A S E III T R A N S P O R T -

E R S

M any phase I and phase I I enzyme inducers share

common mechanisms of t ranscr ipt ional act ivat ion and

share a s imi lar bat tery of genes that are coordinately

regulated. Many phase I I metabol i tes we re found to be

transported o ut of the cel ls by P-g p, MR Ps, and O ATP2.

Along wi th the phase I and phase I I enzyme induct ion,

pretreatmen ts wi th seve ral types of inducers have b een

shown to al ter the excret ion of xenobiot ics, which impl ies

that phase I I I t ransport processes may also be s imi lar ly

regulated. Wh ether these pha se I and pha se I I enzyme

inducers coordinately regulate the so-cal led phase III

t ransporter genes requires further studies, and suchinformat ion wou ld add to o ur knowledge of the disposi t ion

and el imination of xenobiotics.

3-methylcholanthrene (3MC) can induce the expression

of C Y P 1 A 1 C Y P I A 2 and C Y P 1 B 1 by act ivat ing the AhR

regulat ing t ranscr ipt ion of the CYP1 genes. C Y P I A 1 is

undetectable in the l iver of control rats but was found to

be highly induced in the l iver of 3MC treated rats.

Induction of C Y P I A 2 and C Y P I B 1 were also observed in

the l i vers f rom ra ts t reated w i th 3M C (Rushmore and

Kon g, 2002). Ind uct io n of several phase I I enzym es,

U G T 1 A 6 G S T A 1 G S T A 2 and G S T M was a lso observed

in the l iver recovered f rom rats t reated w i th 3M C. 3M C isknown to induce expression of the UDP-glucuronosyl

t ransferase gene U G T 1 A 6 (Bock et a l . 1 9 9 8 ) a n d

glutathione-S-transferase gene GSTA1 (Rushmore e t a L

1990) by an AhR-dependent mechanism (Rushmore and

Kong, 2002) . The G S T A 2 and G S T M I genes are both

induced by the C Y P 1 A 1 epoxide and hydroxylated

metabol i te(s) of 3MC. B oth genes contain an ARE do main

in thei r prom oter re gion s. This c is -a c t in g element has

been show n to be responsive to the d iol metabol i tes of

3MC that can redox cycle and produce a pro-oxidat ive

env ironment (Rushmore and Ko ng, 2002) , p resumably

analogous to the electrophil ic actions of phenolic anti-



Regulat ion of Drug Metabol ism and Drug Transpor t 261

oxidants BH A or tBH Q as de scr ibed before. The glutathione-

S- t ransferases G S T A 2 and G S T M 1 were previously

obs erve d to be 3MC - inducible in cul tured rat hepatocytes

( M a h e o et aL 1997) . H igh leve ls o f mdr mRNAs were

observed by Nor thern blot t ing in two independent rat l iver

epi thel ia l (RLE) cel l l ines af ter t reatment with 3MC. 3MC-mediated m d r m R N A induc t i on w as dem ons t r a t ed t o be

dose-dependent , i t occurred through enhanced expression

of the mdr 1 gene, and paral le led the induct ion of the P-

gp protein expression (Fardel et aL 1996) .

Phenobarbi ta l is a t ranscr ipt ional inducer of the rat

C Y P 2 B 1 C Y P 2 B 2 a n d C Y P 3 A 1 genes . CAR is a nuc lear

receptor t ha t in te rac ts w i th RXR to fo rm CAR-RXR

heterod imers, wh ich b ind to the PBR E in respon se to

phenobarbi ta l t reatment . C Y P 2 C 7 is a lso repor ted to be

induced by phenobarbi ta l , but pr imar i ly in female rather

than in male rats (Honkakoski and Negishi , 1997;

Rush mo re and Kong, 2002; Waxman, 1999) . Induc tion o f

severa l phase I I enzymes was observed a f te r t rea tment

with phenobarbi ta l . A s igni f icant increase in the speci f ic

mR NA for m ic rosomal epox ide hydro lase (EHm ) , U G T 2 B 1

G S T A 1 G S T A 2 G S T A 3 and G S T M 1 wa s a lso observed

in the l ivers recovered f rom rats t reated with phenobar-

bi ta l . Phenobarbi ta l is known to induce the expression of

C Y P 2B gene by t he C A R - dependen t m echan is m . N o

PBRE sequence has been ident i f ied in t he promoters fo r

any o f t he phase I I enzymes to da te . I n add i t ion to t he

phas e I and ph ase I I enzym e induc tion , M RP2 expression

wa s s igni f icant ly induced by Phenobarbi ta l (Staudinger e taL 2003) . M RP3 w as a lso repor ted to be induced by 1 ,4-

bis[2-(3,5-dichloropyr idy loxy)]benzene (TCPO BOP ), a CA R

and CYP2B inducer . However , t he data sugges ted tha t

CAR may not p lay a key role in phenobarbi ta l- induced

M R P 3 ( X iong et a l . 2002) .

E ighteen di f ferent microsomal enzyme inducers inc lud-

ing TCD D, indole-3-carbinol , phenoba rbi ta l , d ia l ly l sul f ide,

s p i r ono lac t one , dex am e t has one , d ie t hy lhex y lph t ha la t e ,

ethoxyquin, o l tipraz, and acety lsal icy lic acid were se lected

based upon s ix major p roposed mechan isms o f d rug-

metabo l iz ing enzyme induc t ion (AhR l igands , CAR

act ivators, PXR l igands, PPAR l igands, EpRE act ivators,and CYP2E1 inducers) , and they did not markedly

inc rease the express ion o f MRP1 or MRP2 (Cher r ing ton

e t a L 2002) . How ever , MR P3 expression wa s s igni ficant ly

increased by each of the CAR act ivators (phenobarbi ta l ,

390 ; 2,2 ' ,4,4 ' ,5-pentachlorobiphenyl (PCB99) , 580 ;

and dial ly l sul f ide, 540 over cont rol) , and an EpR E

act ivator o lt ipraz (6 70 ove r cont rol) in the l ivers of the

rats. MRP3 was not s imi lar ly induced in k idney and large

intest ine, demonst rat ing that the coordinate inducibi l i ty of

MRP3 may be speci f ic to the l iver . Addit ional evidence

sugg es ts tha t M RP3, wh ich is unde r the t ranscr ip t iona l

regulat ion of CAR, may have l iver -speci f ic induct ion of

M R P 3 by C A R ac t i v a t o r s , bec aus e C A R i s ex p r es s ed

almost exclusively in l iver . The authors conclude that rat

hepat ic MRP3 is induced by CAR ac t iva tors , t hus

enhanc ing the vec tora l excre t ion o f some phase I I

metabol i tes f rom the l iver to the blood (Cherr ington et aL

2002) . CAR has bee n descr ibed as a ce l lu la r senso r t ha tis capable of responding to chemical tox ic i ty and

med iat ing C YP 2B family induct ion (Honkako ski et a l .

1998b ; K aw am ot o e t a L 1999; Sueyoshi e t a L 1999) .

Act ivat ion of th is cel lu lar sensor leads to an increase

ex p r es s ion o f M R P 3 , w h i c h m ay l ead t o an enhanc ed

abi l i ty of the l iver to el iminate organic anions into the

sinusoidal b lood, thereb y reducing h epat ic tox ic i ty .

O A TP 2 l eve ls w e r e dec r eas ed 56 t o 72 by t he A hR

l igands (TCDD, indole-3-carbinol , and b-naphthof lavone) ,

increased 84 to 132 by the CA R ligands (phenoba rbi ta l ,

d ia l ly l sul f ide, and PC B 99) , increased 230 to 36 0 by

PXR l igands (PCN, spironolactone, and dexamethasone) ,

and no changes on OATP2 leve ls by PPAR l igands and

AR E/EpR E ac tiva tors were observed (Guo e t a L 2002a,

2002b) . There was no cor re la t ion between Oatp2 mRNA

levels with the al tered OATP2 protein levels, for example,

among the PXR l igands , on ly PCN inc reased oatp2

mR NA leve ls , bu t sp i rono lactone and dexa me thasone d id

not . Fur thermore, o nly PCN, bu t not spironolactone and

dexam ethasone, increased the t ranscript ion of the oatp2

gene as s how n by the i nc reas e am oun t o f m R N A . Thes e

authors conc luded tha t OATP2 may be coord ina ted

regu la ted by the PXR-CYP3A inducers , and tha t t heregu la t ion o f OATP2 by these inducers occu rs a t bo th the

t ranscr ipt ional a nd post - translat ional levels (Guo et a l .

2002a, 2002b) .

In summary, the impor tance of the coordinated

regulat ion of the p has e I II t ransp or ter wi th the ph ase I and

ph ase I I drug m etabol iz ing enz ym es nee ds fur ther invest i -

gat ion. The addit ion of phase I l l t ranspor ters, such as P-

gp, MRPs and OATPs, regu la t ion o f gene express ion by

receptors such as PXR and CAR, w i l l lend bet te r under -

standing to the biological funct ions of PXR and CAR as a

chem ical /xenobiot ics sensor , however , mos t impor tant ly ,

as a mean o f manag ing the pro tec t ion o f t he drug orxenobiot ics exposure f rom the environment . Future studies

wi l l shed l ight on the roles of other receptors, t ranscr iption

factors and s ignal ing cascades in the coordinated regu-

lat ion of ph as e I, I I an d I II dru g metabo lism/transport by

endoge nous c om pound s as w el l as by ex ogenous agen t s

including environmental and nut r it ional, in the tr igger ing of

d isease s and or tox ici ties induced by these chemica ls .

CKNOWLEDGEMENT

Suppor ted in par t by grant R01-CA-094828 f rom

National Inst itutes of Health.



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