Oncostatin M down-regulates basal and induced cytochromes P450 in human hepatocytes.
The effects of oncostatin M on the expression of different cytochrome P450 (CYP) isozymes has been investigated in human hepatocytes. The dose-response and time-course analyses of effects on CYP1A2 and CYP3A4 isozymes revealed that maximal inhibition was reached after 48 hr of exposure of human hepatocytes to 25 units/ml oncostatin M. Reductions in CYP1A2 and CYP3A4 activity produced by oncostatin M correlated with decreases in protein content, de novo protein synthesis and specific mRNA levels, thus suggesting that oncostatin M could down-regulate CYP expression at the transcriptional level. The inhibitory potency of oncostatin M on CYP expression was compared with that of other cytokines belonging to the interleukin-6 receptor family (interleukin-6, interleukin-11 and leukemia inhibitory factor), and interferon-gamma, which is recognized to inhibit human CYP expression, and granulocyte colony-stimulating factor, a cytokine that shares structural homology with the interleukin-6 family but has a different transduction signal. Maximal reductions in CYP1A2 activity were reached after 48 hr of treatment with cytokines. At that time, oncostatin M showed the highest inhibitory effects on CYP1A2 activity (38% of control), followed by interferon (49% of control) and interleukin-6 (60% of control), whereas minor effects were produced by the other cytokines (74-80%). Comparable decreases were observed for CYP2A6, CYP2B6 and CYP3A4 activities. Enzymatic activity and de novo protein synthesis of 3-methylcholanthrene-induced CYP1A2 and dexamethasone-induced CYP3A4 were also reduced to a much greater extent by oncostatin M than by other cytokines. The results show that oncostatin M is the most effective cytokine in down-regulating CYP isozymes in human hepatocytes, and its effects were evident even after removal of the cytokine from the culture medium.
Guillén
M I
MI
Unidad de Hepatolog-ia Experimental, Centro de Investigaci-on, Hospital Universitario La Fe, Valencia, Spain.
Donato
M T
MT
Jover
R
R
Castell
J V
JV
Fabra
R
R
Trullenque
R
R
Gómez-Lechón
M J
MJ
D000328:Adult; D000368:Aged; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D004790:Enzyme Induction; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D011506:Proteins / Q000187:drug effects
D016207:Cytokines; D006131:Growth Inhibitors; D009573:Nitrites; C508351:OSM protein, human; D010455:Peptides; D011506:Proteins; D053683:Oncostatin M; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human