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Selective Downregulation of Hepatic Cytochrome P450 Expression and Activity in a Rat Model of Inflammatory Pain

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Purpose.

This study was designed to examine the effect of Freund’s complete adjuvant (FCA)-induced inflammation on liver P450 expression and activities in the first 7 days that followed a single FCA injection in the rat hindpaw.

Methods.

Rats were humanely sacrificed at regular time points, plasma and liver samples were collected, liver mRNA extracted, and liver microsomes prepared.

Results.

FCA injection led to the development of an acute inflammatory response evidenced by paw edema and increased alpha-1-acid glycoprotein (AGP) and total-nitrite (NOx) plasma concentrations. Plasma IL-6 levels were significantly higher in FCA-treated rats than in controls at 8 h post-FCA. Within 24 h, these changes were accompanied by a rapid decrease in total P450 contents in FCA-treated rat liver and the selective downregulation of specific CYP isoforms, as illustrated by decreased mRNA levels (CYP2B, CYP2C11, CYP3A1, and CYP2E1), protein contents (CYP2B, CYP2C11, and CYP2E1) or catalytic activities (CYP2C6, CYP2C11, and CYP2E1). CYP3A1 mRNA levels were severely decreased by FCA administration, whereas CYP3A2 mRNA and protein levels remained unchanged.

Conclusions.

These early biochemical and metabolic modifications may have pharmacokinetic and pharmacodynamic consequences when hepatically cleared drugs are administered to FCA-treated rats, especially within the first 24–72 h post-FCA.

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Abbreviations

AGP:

α1-acid glycoprotein

ANOVA:

analysis of variance

API-ES:

atmospheric pressure ionization—electrospray

CYP:

cytochrome P450 isoform

DM:

dextromethorphan

DEX:

dextrorphan

DF:

diclofenac

ELISA:

enzyme-linked immunosorbent assay

FCA:

Freund’s complete adjuvant

HPLC/MS:

high-performance liquid chromatography/mass spectrometry

4-OH-DF:

4-hydroxy-diclofenac

IL:

interleukin

LOQ:

limit of quantification

LPS:

lipo-polysaccharide (E. coli endotoxin)

M:

mass of the parent compound

MH+:

molecular ion

m/z:

mass over charge ratio

MS:

mass spectrometry

NADPH:

nicotinamide adenosine diphosphate reduced form

NOx:

total nitrite levels; P450; cytochrome P450

SIM:

selected ion monitoring

SDS:

sodium dodecyl sulfate

TNF-α:

tumor necrosis factor-α

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Authors and Affiliations

  1. Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada

    Denis Projean, Jean-Louis Brazier & Julie Ducharme

  2. AstraZeneca R & D Montréal, Information not available, Ville St-Laurent, Québec, Canada

    Denis Projean, Sophie Dautrey, Huy Khan Vu, Thierry Groblewski & Julie Ducharme

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  1. Denis Projean
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Correspondence to Julie Ducharme.

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Projean, D., Dautrey, S., Vu, H. et al. Selective Downregulation of Hepatic Cytochrome P450 Expression and Activity in a Rat Model of Inflammatory Pain. Pharm Res 22, 62–70 (2005). https://doi.org/10.1007/s11095-004-9010-6

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