Selective downregulation of hepatic cytochrome P450 expression and activity in a rat model of inflammatory pain.
OBJECTIVE
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, CYP2CI1, 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.
Projean
Denis
D
Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada.
Dautrey
Sophie
S
Vu
Huy Khan
HK
Groblewski
Thierry
T
Brazier
Jean-Louis
JL
Ducharme
Julie
J
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D018836:Inflammation Mediators / Q000008:administration & dosage; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D010146:Pain / Q000201:enzymology* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D065607:Cytochrome P-450 Enzyme Inhibitors; D018836:Inflammation Mediators; D005620:Freund's Adjuvant; D003577:Cytochrome P-450 Enzyme System