SPECIES-DIFFERENCES IN RESPONSIVENESS TO 1,4-BIS[2-(3,5-DICHLOROPYRIDYLOXY)]-BENZENE, A POTENT PHENOBARBITAL-LIKE INDUCER OF MICROSOMAL MONO-OXYGENASE ACTIVITY

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 .phi. 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 .apprx. 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 4 strains of mice and Syrian golden hamsters, TCPOBOP (3 mg/kg) was a potent inducer of hepatic aminopyrine N-demethylase activity but 4 strains of rats and guinea pigs failed to respond. This greatly diminished potency of TCPOBOP in the rat (ED50, 1.2 .times. 10-4 mol/kg) compared with the mouse (ED50 = 4.9 .times. 10-7 mol/kg) is not attributable to 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, 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.