Regulation of cytochrome P-450 monooxygenases in the mouse
Recently, the compound 1,4-bis(2-(3,4-dichloropyridyloxy)) benzene (TCPOBOP) has been identified as a highly potent phenobabital-like agonist in mice. This finding has led to the suggestion that a receptor-mediated process may govern the induction of cytochrome P-450 monooxygenases by phenobarbital and phenobarbital-like agonists. This dissertation examines: (1) the effects of structural alterations of the TCPOBOP molecule on enzyme induction activity, (2) the induction response to phenobarbital and TCPOBOP among inbred mouse strains, (3) the spectrum of monooxygenase activities induced by phenobarbital and TCPOBOP compared to 3-methylcholanthrene, isosafrole and pregnenolone 16..cap alpha..-carbonitrile (PCN) and (4) the binding of (/sup 3/H) TCPOBOP in hepatic cytosol. Changes in the structure of the pyridyloxy or benzene rings markedly affect enzyme induction activity and provide additional indirect evidence for a receptor-mediated response. An evaluation of monooxygenase induction by TCPOBOP for 27 inbred mouse strains and by phenobarbital for 15 inbred mouse strains failed to identify a strain which was completely nonresponsive to these compounds, although several strains exhibited decreased responsiveness for select monooxygenase reactions. TCPOBOP, PCN and phenobarbital were all found to significantly increase the rate of hydroxylation of testosterone at the 2..cap alpha..-, 6..beta..- and 15..beta..- positions but only TCPOBOP and phenobarbital dramatically increased the rate of pentoxyresorufin O-dealkylation. The results demonstrates that TCPOBOP most closely resembles phenobarbital in its mode of monooxygenase induction in mice. Sucrose density gradient analysis of (/sup 3/H) TCPOBOP-hepatic cytosol incubations failed to identify specific, saturable binding of (/sup 3/H) TCPOBOP to cytosolic marcomolecular elements.
- Research Organization:
- Texas A and M Univ., College Station (USA)
- OSTI ID:
- 6994795
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
CYTOCHROME OXIDASE
BIOCHEMICAL REACTION KINETICS
ENZYME INDUCTION
DRUGS
STRUCTURE-ACTIVITY RELATIONSHIPS
ENZYME ACTIVITY
HYDROXYLATION
MICE
PHENOBARBITAL
RECEPTORS
TESTOSTERONE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANDROGENS
ANDROSTANES
ANESTHETICS
ANIMALS
ANTICONVULSANTS
AZINES
BARBITURATES
CENTRAL NERVOUS SYSTEM DEPRESSANTS
ENZYMES
GENE REGULATION
HAEM DEHYDROGENASES
HETEROCYCLIC COMPOUNDS
HORMONES
HYDROXY COMPOUNDS
HYPNOTICS AND SEDATIVES
ISOTOPE APPLICATIONS
KETONES
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
OXIDOREDUCTASES
PROTEINS
PYRIMIDINES
REACTION KINETICS
RODENTS
STEROID HORMONES
STEROIDS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques