Enzyme Induction

Several mechanisms are involved in P450 enzyme induction, which results in an increase in total enzyme concentration either by increasing the rate of expression of the enzyme or by decreasing the rate of degradation of the enzyme. These mechanisms are very complex and involve several transcriptional factors and elements in the cytosol and nucleus. Here, we focus on the critical components relevant to several major P450 isoforms: the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR). PXR and CAR regulate P450 isoforms to different extents:

PXR: CYP3A4 > CYP2B6 > CYP2C CAR: CYP2B6 > CYP2C > CYP3A4

See Table 5.6.

Table 5.6. Phase I and Phase II DMEs and transporters induced by AhR, CAR, and PXR

Receptor

Phase I enzymes

Phase II enzymes

Transporters

AhR

CYP1A1, 1A2,

UGT1A1, GSTA2,

BCRP

CYP1B1, ALDH

SULT1A1

CAR

CYP2A, CYP2B,

UGT1A1, SULT1A1

OATP2, MRP2,

CYP2C, CYP3A

MRP3

PXR

CYP2B, CYP2C,

UGT1A1, GSTA2,

MDR1, MRP2,

CYP3A

SULT2A1

OATP, OCT1

Table 5.7. Chemical inducers of P450 isoforms in vitro

P450 isoform

Receptor

Inducer

[Inducer] (|iM)

EC50 (|iM)

Emax (Fold induction)

CYP1A2

AhR

Omeprazole

25-100

0.23 ± 0.15a

2.4 ± 0.9a, 14-24

P-Naphthoflavone

33-50

4-23

3-Methylcholanthrene

1-2

6-26

CYP2B6

CAR > PXR

Phénobarbital

500-1,000

58 ± 96a

7.6 ± 1.8a, 5-10

CYP3A4/5

PXR> CAR

Rifampin

10-25

0.85 ± 0.75a

12±3a, 4-31

aKato et al. 2005 Drug Metabolism Pharmacokinet 20:236-243

All the other data from FDA's Draft Guidance for Industry on Drug Interaction Studies (2006)

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