1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and related compounds as inducers of hepatic monooxygenases. Structure-activity effects.
1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) resembles phenobarbital (PB) in its mode of induction of the hepatic drug-metabolizing enzymes in mice. The structural features of this molecule include: a linear tricyclic aromatic ether ring system, an internal 1,4-disubstituted benzene ring and two 3,5-dichloropyridyloxy substituents. Ten analogs of TCPOBOP have been synthesized and their activities as microsomal enzyme inducers evaluated. Dose-response induction of mice hepatic microsomal cytochrome P-450, aldrin epoxidase and dimethylaminoantipyrine N-demethylase gave ED50 values for TCPOBOP and five homologs. The results illustrate that changes in the structure of the pyridyloxy ring markedly affect enzyme induction activity. The order of activity for the substituents was 3,5-dibromopyridyloxy approximately 3,5-dichloropyridyloxy greater than 5-bromopyridyloxy approximately 5-chloropyridyloxy greater than 3-chloropyridyloxy greater than pyridyloxy. In addition, the effects of altered substitution pattern of the benzene ring and structural alterations of the internal ring moiety were evaluated by measuring hepatic microsomal coumarin hydroxylase activity. The results confirm the microsomal monooxygenase enzyme induction activity of TCPOBOP, and the observed structure-dependent potencies of several related homologs support a receptor-mediated mechanism of action for the process.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011725:Pyridines; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C019647:aldrin epoxidase; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D010089:Oxidoreductases, N-Demethylating; C023680:dimethylaminoantipyrine N-demethylase; D010634:Phenobarbital