Molecular Pharmacology, Vol 20, 442-450, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Species Differences in Responsiveness to 1,4-Bis[2-(3,5-dichloropyridyloxy)]-benzene, a Potent Phenobarbital-Like Inducer of Microsomal Monooxygenase Activity

¹ McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

1,4-Bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP), previously shown to be an extremely potent inducer of the phenobarbital pleiotropic response in mice, was surprisingly ineffective in the rat. Hepatic aminopyrine N-demethylase, benzphetamine N-demethylase, NADPH-cytochrome c reductase, microsomal epoxide hydrolase and aldehyde dehydrogenase activities, cytochrome P-450, and liver weight were all increased in the rat by sodium phenobarbital, but not by TCPOBOP at a dose of 10 mg/kg (equivalent to 50 times the mouse ED₅₀). At higher doses, TCPOBOP did produce an increase in hepatic benzphetamine N-demethylase activity, but this response plateaued at about 40% of the maximal response produced by phenobarbital. TCPOBOP appears to have diminished potency and intrinsic activity in the rat, but it does not antagonize the effect of phenobarbital (i.e., act as a partial agonist). In four strains of mice and Syrian golden hamsters, TCPOBOP (3 mg/kg) was a potent inducer of hepatic aminopyrine N-demethylase activity, but four strains of rats and guinea pigs failed to respond. This greatly diminished potency of TCPOBOP in the rat (ED₅₀ 1.2 x 10^-4 moles/kg) compared with the mouse (ED₅₀ = 4.9 x 10^-7 moles/kg) is not attributable to (a) a rapid metabolism or excretion, because in both species [³H] TCPOBOP has a long half-life and is stored primarily as the parent compound; or (b) a toxic effect preventing the hepatic induction response. The species difference in sensitivity to TCPOBOP appears to be due to some evolutionary change affecting the mechanism of induction by TCPOBOP but not by phenobarbital.

This article has been cited by other articles:

				K. Kobayashi, Y. Yamanaka, N. Iwazaki, I. Nakajo, M. Hosokawa, M. Negishi, and K. Chiba IDENTIFICATION OF HMG-CoA REDUCTASE INHIBITORS AS ACTIVATORS FOR HUMAN, MOUSE AND RAT CONSTITUTIVE ANDROSTANE RECEPTOR Drug Metab. Dispos., July 1, 2005; 33(7): 924 - 929. [Abstract] [Full Text] [PDF]

				K. Yoshinari, T. Sato, N. Okino, J. Sugatani, and M. Miwa Expression and Induction of Cytochromes P450 in Rat White Adipose Tissue J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 147 - 154. [Abstract] [Full Text] [PDF]

				G. M. Ledda-Columbano, M. Pibiri, D. Concas, F. Molotzu, G. Simbula, C. Cossu, and A. Columbano Sex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand, TCPOBOP Carcinogenesis, June 1, 2003; 24(6): 1059 - 1065. [Abstract] [Full Text] [PDF]

				P. Honkakoski, R. Moore, J. Gynther, and M. Negishi Characterization of Phenobarbital-inducible Mouse Cyp2b10 Gene Transcription in Primary Hepatocytes J. Biol. Chem., April 19, 1996; 271(16): 9746 - 9753. [Abstract] [Full Text] [PDF]

				Y. Paquet, E. Trottier, M.-J. Beaudet, and A. Anderson Mutational Analysis of the CYP2B2 Phenobarbital Response Unit and Inhibitory Effect of the Constitutive Androstane Receptor on Phenobarbital Responsiveness J. Biol. Chem., December 1, 2000; 275(49): 38427 - 38436. [Abstract] [Full Text] [PDF]