TY - JOUR
T1 - 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and related compounds as inducers of hepatic monooxygenases. Structure-activity effects
AU - Kelley, Michael
AU - Lambert, Iain
AU - Merrill, Jill
AU - Safe, Stephen
N1 - Funding Information:
Acknowledgements--The financial assistance of the Texas Agricultural Experiment Station (No. 6376) and the help of Lorna Safe and Bozena Zmudzka are gratefully appreciated.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1985/10/1
Y1 - 1985/10/1
N2 - 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 ≈ 3,5-dichloropyridyloxy > 5-bromopyridyloxy ≈ 5-chloropyridyloxy > 3-chloropyridyloxy > 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.
AB - 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 ≈ 3,5-dichloropyridyloxy > 5-bromopyridyloxy ≈ 5-chloropyridyloxy > 3-chloropyridyloxy > 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.
UR - http://www.scopus.com/inward/record.url?scp=0022244889&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0022244889&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(85)90722-1
DO - 10.1016/0006-2952(85)90722-1
M3 - Article
C2 - 4052094
AN - SCOPUS:0022244889
SN - 0006-2952
VL - 34
SP - 3489
EP - 3494
JO - Biochemical pharmacology
JF - Biochemical pharmacology
IS - 19
ER -