Interleukin-1 beta differentially represses drug-metabolizing enzymes in arthritic female rats.
Experimental arthritis and inflammation have been reported to reduce liver cytochrome P-450-dependent mono-oxygenase activities with subsequent impairment of drug metabolism. Interleukin-1 beta (IL-1) is among the proven mediators of both inflammation and P-450 decrease, although some paradoxical effects were sometimes reported in experimental models of arthritis. The aim of the present study was to evaluate the main liver drug-metabolizing isoenzymes during established collagen-induced arthritis in rats, and to investigate whether a systemic IL-1 treatment was able to mimic or sometimes to reverse the influence of the inflammatory process on these enzymes. Arthritis was induced on day 0 by type II collagen and a low dose (0.2 mg) of N-acetylmuramyl-L-alanyl-D-isoglutamine, and human recombinant IL-1 was administered s.c. at the daily dose of 0.02, 0.2 or 2.0 micrograms per arthritic rat, from day 21 to 25 and on day 28. Ethoxyresorufin-O-deethylation was depressed 6-fold in arthritic rat liver microsomes and the highest dosage of IL-1 potentiated this depression. Pentoxyresorufin-O-deethylation decreased by 50% in arthritic rat, a dose-dependent decrease being observed after IL-1 treatment. Progesterone 6 beta-hydroxylation and P-450 IIIA protein increased by 2-fold in both untreated arthritic rat liver microsomes and those treated by the lowest dose of IL-1. The two higher doses decreased this activity, vs. the dose, to reach the naive level. Lauric acid hydroxylation increased 2-fold in arthritic rat and was further potentiated by IL-1. UDP glucuronosyl transferase IA2 activity was increased 2-fold in arthritic rats, with subsequent decrease after 2.0 micrograms of IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Ferrari
L
L
Centre du Médicament, URA CNRS 597, Faculté de Pharmacie, Nancy, France.
Jouzeau
J Y
JY
Gillet
P
P
Herber
R
R
Fener
P
P
Batt
A M
AM
Netter
P
P
D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000818:Animals; D001168:Arthritis / Q000201:enzymology*; D015153:Blotting, Western; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004794:Enzyme Repression / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D010105:Oxygenases / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D011920:Rats, Inbred WF; D012737:Sex Factors
D007375:Interleukin-1; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D014453:Glucuronosyltransferase