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Oncostatin M down-regulates basal and induced cytochromes P450 in human hepatocytes
M I Guillén1, M T Donato, R Jover
1Unidad de Hepatolog-ia Experimental, Centro de Investigaci-on, Hospital Universitario La Fe, Valencia, Spain.
Abstract:
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.
Insights
Oncostatin M significantly down-regulates cytochrome P450 (CYP) isozymes in human hepatocytes, impacting drug metabolism. This cytokine demonstrates potent inhibition of CYP expression at the transcriptional level, exceeding other tested cytokines.
Area of Science:
- Pharmacology
- Hepatology
- Molecular Biology
Background:
- Cytochrome P450 (CYP) enzymes are crucial for drug metabolism in the liver.
- Cytokines can modulate the expression of CYP isozymes, affecting drug efficacy and toxicity.
- Understanding cytokine-mediated regulation of CYP is essential for personalized medicine and drug development.
Purpose of the Study:
- To investigate the effects of oncostatin M on the expression of various cytochrome P450 (CYP) isozymes in human hepatocytes.
- To compare the inhibitory potency of oncostatin M with other cytokines on CYP expression.
- To elucidate the mechanism by which oncostatin M affects CYP expression.
Main Methods:
- Human hepatocytes were exposed to varying doses and durations of oncostatin M.
- Expression and activity of CYP isozymes (CYP1A2, CYP3A4, CYP2A6, CYP2B6) were measured.
- De novo protein synthesis and specific mRNA levels were analyzed.
- Inhibitory effects were compared with interleukin-6, interleukin-11, leukemia inhibitory factor, interferon-gamma, and granulocyte colony-stimulating factor.
Main Results:
- Oncostatin M maximally inhibited CYP1A2 and CYP3A4 expression after 48 hours of exposure.
- Reductions in CYP activity correlated with decreased protein synthesis and mRNA levels, indicating transcriptional down-regulation.
- Oncostatin M exhibited the strongest inhibitory effect on CYP1A2 activity compared to other cytokines.
- Comparable inhibitory effects were observed for CYP2A6, CYP2B6, and CYP3A4.
Conclusions:
- Oncostatin M is a potent inhibitor of CYP isozyme expression in human hepatocytes.
- The mechanism involves down-regulation at the transcriptional level.
- Oncostatin M's effects on CYP regulation are more pronounced than those of other tested cytokines, highlighting its significance in drug metabolism modulation.