Repression of cytochrome P450 by cytokines: IL-1 beta counteracts clofibric acid induction of CYP4A in cultured fetal rat hepatocytes.
Interleukin-1 is known to repress a number of hepatic drug-metabolizing enzymes in rats and humans. The effect of interleukin-1 beta on lauric acid 12-hydroxylase (CYP4A family) was studied in cultured fetal rat hepatocytes after clofibric acid induction. Dexamethasone was used as an agent promoting differentiation and long-term maintenance of active hepatocytes. Dexamethasone and clofibric acid in combination allowed maximal (13.5-fold) induction of CYP4A1. Lauric acid 12-hydroxylase activity was found to increase with time in culture. Interleukin-1 beta adversely affected P4504A clofibric acid-induced activity, totally eliminating the effect of induction at doses exceeding 5 ng/ml. This repression/inhibition was dose-dependent. The mechanism by which interleukin-1 beta prevents the development of cytochrome P4504A activity is unclear.
Parmentier
J H
JH
Centre du Médicament, URA CNRS 597, Université de Nancy I, France.
Kremers
P
P
Ferrari
L
L
Batt
A M
AM
Gielen
J E
JE
Siest
G
G
D000818:Animals; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D007375:Interleukin-1; D002995:Clofibric Acid; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D010634:Phenobarbital