title: Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture.
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 EC(50) values that differed by isoenzyme. Some EC(50) 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 EC(50) 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.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen, Inc., Seattle, WA 98119, USA. ldickman@amgen.com
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Dickmann
authors.forename: Sonal K
authors.initials: SK
authors.lastname: Patel
authors.forename: Dan A
authors.initials: DA
authors.lastname: Rock
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: J Greg
authors.initials: JG
authors.lastname: Slatter
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000276:immunology; D018929:Cell Culture Techniques; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology*; D007527:Isoenzymes; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis; D000685:Serum Amyloid A Protein / Q000276:immunology; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D015850:Interleukin-6; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D019947:Receptors, Interleukin-6; D000685:Serum Amyloid A Protein; D002097:C-Reactive Protein; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human