Evidence for induction of hepatic microsomal cytochrome P-450 by cimetidine: Binding and kinetic studies

Ioannoni B., Mason S.R., Reilly P.E.B. and Winzor D.J. (1986) Evidence for induction of hepatic microsomal cytochrome P-450 by cimetidine: Binding and kinetic studies. Archives of Biochemistry and Biophysics, 247 2: 372-383. doi:10.1016/0003-9861(86)90596-5


Author Ioannoni B.
Mason S.R.
Reilly P.E.B.
Winzor D.J.
Title Evidence for induction of hepatic microsomal cytochrome P-450 by cimetidine: Binding and kinetic studies
Journal name Archives of Biochemistry and Biophysics   Check publisher's open access policy
ISSN 1096-0384
Publication date 1986-01-01
Sub-type Article (original research)
DOI 10.1016/0003-9861(86)90596-5
Volume 247
Issue 2
Start page 372
End page 383
Total pages 12
Subject 1303 Specialist Studies in Education
1304 Biophysics
1312 Molecular Biology
Abstract The interaction of cimetidine with liver microsomes has been examined by spectral and equilibrium partition studies. First, difference spectroscopy has been used to evaluate the proportion of cytochrome P-450 in rat liver microsomes that exhibits an affinity for cimetidine in the pharmacologically relevant, low micromolar range of drug concentration. The value of 0.45 so obtained has confirmed that a substantial proportion of rat liver cytochrome P-450 has a high binding affinity for this drug. Second, a study of the binding of cimetidine to human liver microsomes by difference spectroscopy and partition equilibrium has detected a similar interaction, thus providing direct support for the postulate that the clinically observed impairment of oxidative drug metabolism may be due in part to inhibition of cytochrome P-450 monooxygenase by cimetidine. Hepatic microsomes from cimetidine-pretreated rats have been shown to exhibit elevated cytochrome P-450 specific content but a decreased proportion of sites with high affinity for the drug; this finding has been shown not to be the consequence of cimetidine-mediated, time-dependent, irreversible monooxygenase inhibition. Although cimetidine pretreatment caused enhanced specific activity of 7-ethoxyresorufin O-dealkylation, the specific activities for O-dealkylation of 7-ethoxycoumarin and 4-nitroanisole were decreased, as were those for the N-dealkylation of morphine, ethylmorphine, aminopyrine, and dimethylnitrosamine. Since cimetidine pretreatment was shown to cause no change in the Michaelis constants for oxidation of morphine or 7-ethoxyresorufin, it is argued that these results provide strong presumptive evidence for changes in the relative abundance of isoenzymes catalyzing these various oxidations. Thus, a dual role of cimetidine, acting both as inhibitor and inducer of the cytochrome P-450 system, is proposed to account for the impaired oxidative metabolism of some drugs that occurs during coadministration with this H2-receptor antagonist.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

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