Immunoglobulins and Interleukin-6 Mediated Suppression of Hepatic Drug-Metabolizing Enzymes

Strategic Insights -

Researchers from Amgen have published a study in the journal Drug Metabolism and Disposition, examining the effects of interleukin-6 (IL-6) on drug-metabolizing enzymes in human hepatocyte culture. The study found that IL-6 suppresses the activity of 10 major cytochrome P450 isoenzymes, with varying EC(50) values. The study also showed that a monoclonal antibody directed against IL-6 can abolish or partially block IL-6-mediated suppression of CYP1A2 and CYP3A4 enzyme activity.

Key Takeaways:

  • The study found that IL-6 suppresses the activity of 10 major cytochrome P450 isoenzymes, with EC(50) values that differed by isoenzyme.
  • The 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.
  • The study indicates that experimentation with IL-6 and anti-IL-6 monoclonal antibodies in human hepatocyte primary culture can quantitatively measure cytochrome P450 suppression and desuppression.
  • The complex biology of inflammatory disease may not allow for quantitative in vitro-in vivo extrapolation of these simple in vitro data.

Statistics:

  • 10 major cytochrome P450 isoenzymes were suppressed by IL-6.
  • EC(50) values differed by isoenzyme, with some EC(50) values 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 at supraphysiological concentrations.

Sources:

  • Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metabolism and Disposition, 2011;39(8):1415-22.
  • Amgen Inc., Seattle, WA 98119, United States.