Abstract
The cytokine-mediated suppression of hepatic drug-metabolizing enzymes by inflammatory disease and the relief of this suppression by successful disease treatment have recently become an issue in the development of drug interaction labels for new biological products. This study examined the effects of the inflammatory cytokine interleukin-6 (IL-6) on drug-metabolizing enzymes in human hepatocyte culture and the abrogation of these effects by a monoclonal antibody directed against IL-6. Treatment of human hepatocytes with IL-6 (n = 9 donors) revealed pan-suppression of mRNA of 10 major cytochrome P450 isoenzymes, but with EC50 values that differed by isoenzyme. Some EC50 values were above the range of clinically relevant serum concentrations of IL-6. Marker activities for CYP1A2 and CYP3A4 enzyme were similarly suppressed by IL-6 in both freshly isolated and cryopreserved hepatocytes. IL-6 suppressed induction of CYP1A2 enzyme activity by omeprazole and CYP3A4 enzyme activity by rifampicin but only at supraphysiological concentrations of IL-6. Glycosylated and nonglycosylated IL-6 did not significantly differ in their ability to suppress CYP1A2 and CYP3A4 enzyme activity. A monoclonal antibody directed against IL-6 abolished or partially blocked IL-6-mediated suppression of CYP1A2 and CYP3A4 enzyme activity, respectively. These data indicate that experimentation with IL-6 and anti-IL-6 monoclonal antibodies in human hepatocyte primary culture can quantitatively measure cytochrome P450 suppression and desuppression and determine EC50 values for IL-6 against individual cytochrome P450 isoenzymes. However, the complex biology of inflammatory disease may not allow for quantitative in vitro-in vivo extrapolation of these simple in vitro data.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038679.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- IL-6
- interleukin-6
- IL-6R
- IL-6 receptor
- P450
- cytochrome P450
- APR
- acute-phase response
- NF-κB
- nuclear factor κ-light-chain enhancer of activated B cells
- CAR
- constitutive androstane receptor
- PXR
- pregnane X receptor
- HEK
- human embryonic kidney
- KHB
- Krebs-Henseleit buffer
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- DP
- declustering potential
- CE
- collision energy
- CXP
- collision cell exit potential
- CRP
- C-reactive protein
- SAA
- serum amyloid A
- C/EBP
- CCAAT/enhancer-binding protein
- STAT3
- signal transducer and activator of transcription 3.
- Received February 10, 2011.
- Accepted May 9, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|