Drug Metabolism in Drug Design and Development Basic Concepts and Practice

the cytosol and nucleus, is activated once a ligand binds, then corepressors (R)
are removed and coactivators (A) recruited. At this point, the activated receptor
dimerizes with RXR (translocates to the nucleus) and binds to the response
elements (PXR RE) found within the CYP3A4 promoter region. Recruitment of
additional transcription factors, such as, RNA polymerase, initiates transcrip-
tion of the CYP3A4 mRNA, followed by subsequent translation into active
enzyme.
The mechanism of CAR-mediated gene transcription differs somewhat from
that of PXR. CAR is always activated and is therefore sequestered in the

TABLE 5.6 Nuclear receptors, their activated genes, and common activators for
each receptor.

Nuclear
receptor Target Genes Activators References

AhR CYP1A1/2, CYP1B1,
CYP2S1, UGT1A1,
UGT1A6,
3-hydroxybutyrate
dehydrogenase,
SULT2B

TCDD,aBNF,b

3MC,cCigarette

smoking

Mandal (2005),

Runge-Morris and

Kocarek (2005),

Zhou et al. (2005)

CAR CYP2B6, CYP3A4,
UGT1A1, UGT2B1,
SULT2A1, MRP2,
MRP3, MRP4

Phenytoin, CITCO,d

5 b-pregnane-3,20-dione,

phenobarbital

Honkakoski
(2003), Klaassen
and Slitt (2005),
Moore (2002),
Runge-Morris and
Kocarek (2005),
Zhou (2005)
PXR CYP3A4,CYP2B6,
CYP2C9, GST,
UGT1A1, UGT1A6,
UGT1A9, SULT2A1,
MRP2, MRP3,
MRP5, MDR1

Rifampicin, SR12813,

hyperforin,

clotrimazole,

forskolin

Carnahan and
Redinbo (2005),
Ding and Staudinger
(2005), Honkakoski
(2003), Klaassen
and Slitt (2005),
Moore (2002),
Runge-Morris and
Kocarek (2005),
Zhou (2005)
FXR CYP7A1, UGT2B4,
MDR3, BSEP

GW4064, fexaramine,

TTNPBe

Dixit et al. (2005),

Klaassen and

Slitt (2005),

Zhou (2005)

a2,3,7,8-Tetrachlorodibenzo-p-dioxin.
bb-Naphthoflavone.
c3-Methylcholanthrene.
d6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehydO-(3,4-dichlorobenzyl)oxime.
e(E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid.

ENZYME INDUCTION 123