In Vivo and in Vitro Induction of Cytochrome P450 Enzymes in Beagle Dogs

• DOI: 10.1124/dmd.30.11.1206
• Publication Date: 2003-01-15T23:17:35Z
• Authors: Richard A. Graham; April Downey; Dan Mudra; Linda Krueger; Kathy Carroll; Christopher Cheng...; Ajay Madan; Andrew Parkinson
• Keywords: Beagle; Phenobarbital; Inducer

The aim of this study was to determine the in vitro and vivo effects several prototypical inducers, namely beta-naphthoflavone, 3-methylcholanthrene, phenobarbital, isoniazid, rifampin, clofibric acid, on expression cytochrome P450 (P450) enzymes beagle dogs. For induction study, primary cultures dog hepatocytes were treated with enzyme inducers for 3 days, after which microsomes prepared analyzed activities. male female dogs 4 days (with exception given 14 days), livers removed microsomal activities determined ex vivo. Treatment hepatocyte (n = 3) beta-naphthoflavone or 3-methlychloranthrene resulted up a 75-fold increase 7-ethoxyresorufin O-dealkylase (CYP1A1/2) activity, whereas treatment followed by analysis 24-fold increase. Phenobarbital caused 13-fold 7-benzyloxyresorufin (CYP2B11) activity 9.9-fold Isoniazid had little no effect 4-nitrophenol hydroxylase vitro. Rifampin testosterone 6beta-hydroxylase (CYP3A12) 4.5-fold acid appeared have CYP4A as 12-hydroxylation lauric acid. In general, absolute rates (picomoles per minute milligram protein) reactions catalyzed from cultured (i.e., rates) considerably lower than those liver rates). These results suggest that CYP1A, CYP2B, CYP2E, CYP3A profile resembles observed humans more rats.