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Involvement of CYP2E in 8-Hydroxylation of Theophylline in Mouse Hepatic Microsomes-Difference from Its N-Demethylations
- Source :
- Biological and Pharmaceutical Bulletin. 19:593-598
- Publication Year :
- 1996
- Publisher :
- Pharmaceutical Society of Japan, 1996.
-
Abstract
- We examined which cytochrome P-450 (P-450) species other than CYP1A participates in the oxidative metabolism of theophylline (TP) in mouse hepatic microsomes. Among the three metabolic pathways of TP, only 8-hydroxylation was selectively enhanced by acetone, a potent inducer of CYP2E. We assumed that two P-450 populations with different metabolic ability were involved in this metabolic process, and kinetic analyses revealed that the enhancement was due to the induction of a high-capacity P-450 population. The 8-hydroxylation at a substrate concentration, where most of the total activity was attributed to the catalysis of the high-capacity phase, was markedly impaired by CYP2E inhibitors such as 4-methylpyrazole and aminoacetonitrile, whereas the N-demethylations were little affected by these agents. The activity of TP 8-hydroxylation was significantly correlated with that of p-nitrophenol hydroxylation, a probe for CYP2E, in untreated microsomes. The activities of these oxidative reactions were modified to a similar degree by known enzyme inhibitors with a range of inhibitory potencies and affinity for P-450 isoforms. On the other hand, a relationship between TP N-demethylations and p-nitrophenol hydroxylation was not apparent, but there was a behavioral similarity between the two types of N-demethylations. The results indicated that TP 8-hydroxylation, which accounts for a large portion of TP oxidations, involves CYP2E, and that its N-demethylations are mediated by a common or closely similar P-450 species distinct from CYP2E.
- Subjects :
- Male
Pregnenolone Carbonitrile
Population
Pharmaceutical Science
Mice, Inbred Strains
Hydroxylation
Acetone
Nitrophenols
Mice
chemistry.chemical_compound
Cytochrome P-450 Enzyme System
Theophylline
Oxazines
medicine
Aminoacetonitrile
Animals
Enzyme Inhibitors
Aminopyrine
education
Fomepizole
Pharmacology
chemistry.chemical_classification
education.field_of_study
biology
Cytochrome P450
Cytochrome P-450 CYP2E1
General Medicine
Metabolic pathway
Enzyme
chemistry
Biochemistry
Phenobarbital
Microsomes, Liver
biology.protein
Microsome
Pyrazoles
medicine.drug
Subjects
Details
- ISSN :
- 13475215 and 09186158
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Biological and Pharmaceutical Bulletin
- Accession number :
- edsair.doi.dedup.....6def1d3f6151e23913c5344720f35cf8