Temporal kinetics and concentration–response relationships for induction of CYP1A, CYP2B, and CYP3A in primary cultures of beagle dog hepatocytes

Journal of Biochemical and Molecular ToxicologyVolume 20, Issue 2 p. 69-78 Research Article Temporal kinetics and concentration–response relationships for induction of CYP1A, CYP2B, and CYP3A in primary cultures of beagle dog hepatocytes Richard A. Graham, Corresponding Author Richard A. Graham [email protected] Division of Molecular Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USADivision of Molecular Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USASearch for more papers by this authorLindsey O. Tyler, Lindsey O. Tyler MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorWojciech L. Krol, Wojciech L. Krol MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorIvin S. Silver, Ivin S. Silver MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorLindsey O. Webster, Lindsey O. Webster WW DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorPhilip Clark, Philip Clark WW DMPK, GlaxoSmithKline, King of Prussia, PA 19406, USASearch for more papers by this authorLiangfu Chen, Liangfu Chen WW DMPK, GlaxoSmithKline, King of Prussia, PA 19406, USASearch for more papers by this authorTroy Banks, Troy Banks WW DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorEdward L. LeCluyse, Edward L. LeCluyse CellzDirect, Inc., 480 Hillsboro Street, Suite 130, Pittsboro, NC 27312, USASearch for more papers by this author Richard A. Graham, Corresponding Author Richard A. Graham [email protected] Division of Molecular Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USADivision of Molecular Pharmaceutics, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USASearch for more papers by this authorLindsey O. Tyler, Lindsey O. Tyler MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorWojciech L. Krol, Wojciech L. Krol MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorIvin S. Silver, Ivin S. Silver MV CEDD DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorLindsey O. Webster, Lindsey O. Webster WW DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorPhilip Clark, Philip Clark WW DMPK, GlaxoSmithKline, King of Prussia, PA 19406, USASearch for more papers by this authorLiangfu Chen, Liangfu Chen WW DMPK, GlaxoSmithKline, King of Prussia, PA 19406, USASearch for more papers by this authorTroy Banks, Troy Banks WW DMPK, GlaxoSmithKline, Research Triangle Park, NC 27709, USASearch for more papers by this authorEdward L. LeCluyse, Edward L. LeCluyse CellzDirect, Inc., 480 Hillsboro Street, Suite 130, Pittsboro, NC 27312, USASearch for more papers by this author First published: 13 April 2006 https://doi.org/10.1002/jbt.20118Citations: 17AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Compared to other species, little information is available on the xenobiotic-induced regulation of cytochrome P450 enzymes in the beagle dog. Dogs are widely used in the pharmaceutical industry for many study types, including those that will impact decisions on compound progression. The purpose of this study was (1) to determine the temporal kinetics of drug-induced changes in canine CYP1A, CYP2B, and CYP3A mRNA and enzymatic activity, and (2) to characterize concentration–response relationships for CYP1A2, CYP2B11, and CYP3A12 using primary cultures of canine hepatocytes treated with β-naphthoflavone (BNF), phenobarbital (PB), and rifampin (RIF), respectively. CYP1A1 and CYP1A2 mRNA exhibited maximal expression (12,700-fold and 206-fold, respectively) after 36 h of treatment with BNF. PB treatment, but not RIF treatment, caused maximal induction of CYP2B11 mRNA (149-fold) after 48 h of treatment. CYP3A12 and CYP3A26 mRNA levels were increased maximally after 72 h of treatment with PB and RIF (CYP3A12, 35-fold and 18-fold, and CYP3A26, 72-fold and 22-fold with PB and RIF treatment, respectively). Concentration–response relationships for BNF induced 7-ethoxyresorufin O-dealkylation (EROD) (EC50 = 7.8 ± 4.2 μM), PB induced 7-benzyloxyresorufin O-dealkylation (BROD) (EC50 = 123 ± 30 μM), and PB and RIF induced testosterone 6β-hydroxylation (EC50 = 132 ± 28 μM and 0.98 ± 0.16 μM) resembled the relationship for human CYP induction compared to that of rodent. Interestingly, RIF had no effect on CYP2B11 expression, which represents a species difference overlooked in previous investigations. Overall, the induction of dog CYP1A, CYP2B, and CYP3A exhibits characteristics that are intermediate to those of rodent and human. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:69–78, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20118 Citing Literature Volume20, Issue2April 2006Pages 69-78 RelatedInformation