Molecular Pharmacology, Vol 18, 571-580, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

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
² Department of Chemistry, University of Rochester, Rochester, New York 14627

Sodium phenobarbital, diphenylhydantoin, dichiorophenobarbital, chlordane, mirex, and dieldrin, compounds which produce a similar pleiotropic response in the liver, were compared for their potency to induce hepatic aminopyrine N-demethylase activity in B6D2F₁/J mice. The ED₅₀, the dose which produces one-half the maximum enzyme induction when administered daily for 3 days, for phenobarbital is 1.07 x 10^-4 mol/kg/ day, and for the most potent of these compounds, dieldrin, the ED₅₀ is 8.0 x 10^-6 mol/kg/ day. A new phenobarbital-like compound, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, (TCPOBOP), is 650 times as potent as phenobarbital, with an ED₅₀ of 1.63 x 10^-7 mol/ kg/day. Maximally effective doses of phenobarbital and TCPOBOP, administered alone or in combination, induce hepatic aminopyrine N-demethylase activity, cytochrome P-450, and NADPH-cytochrome c reductase to the same extent. The cytochrome(s) P-450 induced by these three treatments is similar by CO-difference spectra, ethyl isocyanide difference spectra, and SDS-polyacrylamide gel electrophoresis of liver microsomes. Both phenobarbital and TCPOBOP produce an increase in liver weight, proliferation of the smooth endoplasmic reticulum, and induction of microsomal epoxide hydrolase and cytosolic glutathione S-transferase activities. Both compounds induce microsomal monooxygenase activity in the proximal intestines, but not in kidney or skin. A single maximally effective dose of TCPOBOP (3 mg/kg) induces hepatic aminopyrine N-demethylase and microsomal epoxide hydrolase activities in B6D2F₁/J mice for over 20 weeks. Following the administration of a single dose of ³H-TCPOBOP, radioactivity accumulates and is stored primarily in the adipose tissue and to a lesser extent in the liver. The radioactivity extracted from adipose tissue, 30 days after administration of the ³H-TCPOBOP, chromatographed as the parent compound. The hepatic concentration of TCPOBOP, after the administration of an ED₅₀ dose, was estimated to be 1 x 10^-7 M. TCPOBOP is a potent and long-acting phenobarbital-like inducer, a faithful mimic of this pleiotropic response for all measures tested. Despite the lack of a discernable structure-activity relationship among the numerous foreign compounds which evoke the phenobarbital pleiotropic response, the existence of a potent agonist, i.e., TCPOBOP, suggests that this response may be mediated through a specific recognition site.

Note:
ACKNOWLEDGMENT We gratefully acknowledge the help of Dr. Norman Drinkwater for writing a computer program for analyzing the dose-response curves and potency ratio.

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