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The interleukin-2 receptor down-regulates the expression of cytochrome P450 in cultured rat hepatocytes
M Tinel1, M A Robin, J Doostzadeh
1INSERM Unité 24, Hôpital Beaujon, Clichy, France.
Background & Aims:
Interleukin (IL) 2 is used in advanced cancers, but its effects on cytochrome P450 remain unknown. Other cytokines down-regulate hepatic cytochrome P450, but it is not known whether this involves cytokine receptors. The aim of this study was to determine whether the IL-2 receptor is expressed on hepatocytes and whether its activation by IL-2 depresses cytochrome P450 in cultured rat hepatocytes.
Methods:
A monoclonal antibody specific for the rat IL-2 receptor alpha chain was used to label the receptor, whereas effects on cytochrome P450 were determined after 24 hours of culture with human recombinant IL-2 (5000 U/mL).
Results:
The presence of the IL-2 receptor in hepatocytes was shown by immunoblots, flow cytometry, and scanning confocal microscopy. IL-2 caused a 46% decrease in total cytochrome P450; a 35%, 35%, 36%, 26%, and 56% decrease in immunoreactive cytochrome P4501A1, 2B, 2C11, 2D1, and 3A, respectively; and a marked decrease in cytochrome P4503A2 and 2C11 messenger RNAs. Addition to the culture medium of the anti-receptor antibody or the tyrosine kinase inhibitor genistein prevented the IL-2-mediated decrease in cytochrome P450.
Conclusions:
IL-2 down-regulates the expression of cytochrome P450 genes in cultured rat hepatocytes by interacting with its receptor expressed on hepatocytes.
Insights
Interleukin (IL)-2, used in cancer therapy, was found to decrease cytochrome P450 enzyme levels in rat liver cells. This effect is mediated through the IL-2 receptor on hepatocytes, impacting drug metabolism.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Interleukin (IL)-2 is utilized in advanced cancer treatment.
- The impact of IL-2 on cytochrome P450 (CYP450) enzymes, crucial for drug metabolism, is largely unknown.
- Cytokine receptors' role in regulating hepatic CYP450 is not fully understood.
Purpose of the Study:
- To investigate the expression of the IL-2 receptor on hepatocytes.
- To determine if IL-2 activation down-regulates CYP450 activity in cultured rat hepatocytes.
- To elucidate the mechanism of IL-2's effect on hepatic drug metabolism.
Main Methods:
- Hepatocytes were cultured and treated with human recombinant IL-2.
- Immunoblotting, flow cytometry, and confocal microscopy were used to detect the IL-2 receptor alpha chain.
- CYP450 levels and gene expression were quantified, and the effect of anti-receptor antibody and genistein was assessed.
Main Results:
- The IL-2 receptor alpha chain was confirmed on hepatocytes.
- IL-2 treatment significantly reduced total CYP450 levels by 46% and specific isoforms (CYP1A1, 2B, 2C11, 2D1, 3A, 3A2).
- IL-2 markedly decreased messenger RNA levels for CYP3A2 and 2C11, and this effect was blocked by anti-receptor antibody and genistein.
Conclusions:
- Interleukin-2 down-regulates the expression of cytochrome P450 genes in rat hepatocytes.
- This down-regulation occurs via interaction with the IL-2 receptor expressed on the hepatocyte surface.
- The findings suggest potential implications for drug metabolism during IL-2 cancer therapy.
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