Differential effects of human recombinant interleukin-1 beta on cytochrome P-450-dependent activities in cultured fetal rat hepatocytes.
The immunomodulator interleukin-1 beta (IL-1) is one of the major inflammatory mediators. In vivo, it has been reported to depress some rat liver cytochromes P-450 (cytochrome P-450). Our aim was to study those effects in vitro, using cultured fetal rat hepatocytes as a model. Testosterone 6 beta-hydroxylase (cytochrome P-450 IIIA family activity) was not depressed by IL-1 treatments, but its induction by dexamethasone was prevented. The effect was time- and dose-dependent. Ethoxyresorufine-O-deethylase (cytochrome P-450 IA1 activity) decreased after IL-1 treatment, and dexamethasone partially prevented this inhibition. Acute phase effects of IL-1 were assayed by albumin and transferrin secretions. The cell's sensitivity to glucocorticoids was determined by tyrosine-aminotransferase activity. Our data demonstrate that IL-1 was able to prevent the glucocorticoid induction of cytochrome P-450 IIIA involving at least two different mechanisms. This is in agreement with the theory suggesting that the induction of CYPIIIA family by glucocorticoids requires the presence of the glucocorticoid receptor and some other regulatory elements. Other cytochrome P-450-dependent activities (IIA1, IIB1/2, and IIC11) were inhibited by IL-1 treatments, depending on dose and time, but some were also protected by dexamethasone.
Centre du Médicament, URA CNRS 597, Université de Nancy, France.
L
L
Ferrari
P
P
Kremers
A M
AM
Batt
J E
JE
Gielen
G
G
Siest
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism; D014444:Tyrosine Transaminase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000418:Albumins; D065607:Cytochrome P-450 Enzyme Inhibitors; D007375:Interleukin-1; D011994:Recombinant Proteins; D014168:Transferrin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C022724:testosterone 7-alpha-hydroxylase, hamster; D014444:Tyrosine Transaminase