Evaluation of monooxygenase induction as a means of enhancing the yield of the rat liver cytochrome P-450 isoenzyme with high affinity for cimetidine

Ioannoni B., Reilly P.E.B. and Winzor D.J. (1983) Evaluation of monooxygenase induction as a means of enhancing the yield of the rat liver cytochrome P-450 isoenzyme with high affinity for cimetidine. Biochemical Pharmacology, 32 20: 3103-3108. doi:10.1016/0006-2952(83)90256-3


Author Ioannoni B.
Reilly P.E.B.
Winzor D.J.
Title Evaluation of monooxygenase induction as a means of enhancing the yield of the rat liver cytochrome P-450 isoenzyme with high affinity for cimetidine
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
Publication date 1983-10-15
Sub-type Article (original research)
DOI 10.1016/0006-2952(83)90256-3
Open Access Status Not yet assessed
Volume 32
Issue 20
Start page 3103
End page 3108
Total pages 6
Subject 1303 Specialist Studies in Education
2700 Medicine
3004 Pharmacology
Abstract The binding of cimetidine to liver microsomes prepared from untreated rats and rats pretreated with phenobarbitone or 3-methylcholanthrene has been investigated by difference spectroscopy and equilibrium partition methods. In M/15 phosphate buffer, pH 7.9, microsomes from each group of rats yielded markedly biphasic spectral binding curves, which have been interpreted in terms of two independent classes of cytochrome P-450 site with widely differing binding affinities for the drug. Support for such interpretation was provided by the finding that the spectral binding curve for a purified sample of the principal cytochrome P-450 isoenzyme from liver microsomes of phenobarbitone-pretreated rats could be described adequately by a single rectangular hyperbolic relationship, the spectral dissociation constant being indistinguishable experimentally from that for the weaker class of cytochrome P-450 binding site in the corresponding microsomes. The spectral dissociation constants were 2 μM and 80 μM for microsomes from untreated rats; 44 μM and 540 μM for those from phenobarbitone-pretreated rats; and 34 μM and 540 μM for microsomes from rats pretreated with 3-methylcholanthrene. On this basis, both classes of P-450 site in the microsomes from rats subjected to either pretreatment exhibited lower affinity for cimetidine than their counterparts in microsomes from untreated rats. Equilibrium partition studies of the higher-affinity class of microsomal binding site for cimetidine showed that the twofold increase in the cytochrome P-450 content of microsomes effected by 3-methylcholanthrene pretreatment was more than offset by a diminished proportion of the total cimetidine-binding capacity present as the higher-affinity, pharmacologically significant, receptor (18%, cf. 48% in control microsomes); and that phenobarbitone pretreatment resulted in replacement of the high-affinity receptor by one with a threefold weaker cimetidine-binding affinity. Thus the use of these monooxyginase inducers to enhance the cytochrome P-450 content of liver microsomes would seem to offer little potential in the isolation of the isoenzyme with high affinity for cimetidine.
Q-Index Code C1
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import - Archived
 
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