title: Murine collagen antibody induced arthritis (CAIA) and primary mouse hepatocyte culture as models to study cytochrome P450 suppression.
abstract: Changes in cytochrome P450 expression incurred by inflammatory disease were studied in a murine collagen antibody induced arthritis (CAIA) model and compared to bacterial lipopolysaccharide-treated mice and to cytochrome P450 changes in primary mouse hepatocytes following combination treatments with cytokines IL-1β, IL-6, or TNFα. CAIA in female mice increased serum IL-1β, IL-6 and hepatic serum amyloid A (SAA) mRNA and significantly altered cytochrome P450 mRNA and activity levels. Most cytochrome P450 isoforms were down-regulated, although some, such as Cyp3a13, were up-regulated. Cytokine effects on cytochrome P450 levels in mouse hepatocytes were compared at in vitro cytokine concentrations similar to those measured in CAIA mouse serum in vivo. In vivo and in vitro cytochrome P450 suppression by cytokines was congruent for some cytochrome P450 isoforms (Cyp1a2, Cyp2c29, and Cyp3a11) but not for others (cytochrome P450 oxidoreductase (POR) and Cyp2e1). In mouse hepatocytes, IL-6 and IL-1β in combination in vitro caused a synergistic increase in SAA mRNA expression, but not in cytochrome P450 suppression. IL-1β and IL-6 were equipotent in the suppression of cytochrome P450 gene expression, while TNFα caused mild suppression only at the highest concentrations used. TNFα in combination with IL-1β, IL-6, or both had a protective effect against IL-1β and IL-6-mediated cytochrome P450 suppression. When IL-1β or IL-6 was combined with low concentrations of TNFα, several P450 isoforms were induced rather than suppressed. These data highlight the complexities of performing in vitro-in vivo comparisons using disease models for cytochrome P450 regulation by cytokines.
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: Helen J
authors.initials: HJ
authors.lastname: McBride
authors.forename: Sonal K
authors.initials: SK
authors.lastname: Patel
authors.forename: Kent
authors.initials: K
authors.lastname: Miner
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: J Greg
authors.initials: JG
authors.lastname: Slatter
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors