title: Effects of interleukin 1β (IL-1β) and IL-1β/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture.
abstract: Exposure to cytokines can down-regulate hepatic cytochrome P450 enzymes. Accordingly, relief of inflammation by cytokinetargeted drug therapy has the potential to up-regulate cytochrome P450s and thereby increase clearance of co-administered drugs. This study examined the effects of the inflammatory cytokine, interleukin 1β (IL-1β), and IL-1β/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Treatment of hepatocytes with IL-1β revealed suppression of mRNA expression of several clinically important cytochrome P450 isoenzymes, with EC50 values that differed by isoenzyme. Suppression of CYP1A2 activity by IL-1β could not be measured in 3 of 5 donors due to lack of response, and in the two remaining donors the average EC50 was 450 pg/mL. CYP3A activity had an EC50 of suppression of 416 ± 454 pg/mL. Measurable EC50s were obtained for all 5 donors for CYP2C8, 3A4, 3A5, 4A11 and IL-6R mRNA with fold differences which varied between 9.5-fold (CYP2C8) to 109-fold (CYP4A11). When hepatocytes were treated with IL-1β and IL-6 in combination at concentrations which ranged from 1-100 pg/mL, IL-6 was the main determinant of increases in acute phase response marker mRNA and of decreases in CYP3A4 mRNA. There was no synergy between IL-1β and IL-6 in the regulation of cytochrome P450 mRNA when dosed in combination, although the effects of the two cytokines in combination were additive in certain instances. These data indicate that IL-1β and IL-6 both suppress cytochrome P450 mRNA and enzyme levels in vitro and that, at similar physiologically-relevant concentrations in vitro, IL-6 is more potent than IL-1β.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc., 1201 Amgen Court West, 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: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: J Greg
authors.initials: JG
authors.lastname: Slatter
mesh_terms: D018929:Cell Culture Techniques; D004338:Drug Combinations; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000008:administration & dosage*; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D004364:Pharmaceutical Preparations