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 Toxicology
Richard A GrahamE LeCluyse

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 beta-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) (EC(50) = 7.8 +/- 4.2 microM), PB ind...Continue Reading

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Citations

Apr 30, 2010·Pharmaceutical Research·Cuyue Tang, Thomayant Prueksaritanont
Dec 1, 2006·Expert Opinion on Drug Discovery·Jan L WahlstromLarry C Wienkers
Feb 26, 2013·Drug Metabolism Reviews·Marilyn N MartinezLauren Trepanier
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May 6, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·Richard A GrahamEdward L Lecluyse
Sep 17, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Emile P ChenHarma Ellens

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