Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes

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Serval ID
serval:BIB_B6AF1192DEC0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes
Journal
Pharmacogenetics
Author(s)
Rochat  B., Amey  M., Gillet  M., Meyer  U. A., Baumann  P.
ISSN
0960-314X (Print)
Publication state
Published
Issued date
02/1997
Volume
7
Number
1
Pages
1-10
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Feb
Abstract
Using in vitro techniques, the present study demonstrates that CYP2D6, and 3A4 are involved in N-demethylation of citalopram (CIT) enantiomers. Human liver microsome incubations performed with specific inhibitors of these three CYP isozymes have shown up to 60% inhibition of demethylcitalopram production. cDNA expressed human cytochrome P-450 3A4, 2C19 and 2D6 isozymes, but not CYP1A2, were identified to be involved in N-demethylation of CIT enantiomers. Kinetics using cDNA expressed CYP2C19 and CYP3A4 show K(m) values in the same range: 198 microM, 211 microM for CYP2C19 and 169 microM, 163 microM for CYP3A4 for S- and R-CIT demethylation, respectively. In contrast, kinetics using cDNA expressed CYP 2D6 show a K(m) of 18 microM and 22 microM for S- and R-CIT demethylation, respectively. Nevertheless, kinetics using cDNA expressed CYP2C19 and 3A4 have a range of Vmax values ten times higher than that of CYP2D6. For this reason, intrinsic clearance values (Vmax/K(m)) for S- and R-CIT were within a small range for these three isozymes: 0.25 to 0.39 microliter h-1 x pmol-1 of CYP. CYP2D6 has an opposite stereoselectivity in the biotransformation of CIT enantiomers than CYP2C19 and 3A4; the S/R ratios of the intrinsic clearance were 0.71, 1.57 and 1.37, respectively. Taking into account that CYP isozymes are expressed at various levels, CYP2D6, which is expressed at lower levels than CYP2C19 and CYP3A4, plays a minor role in the biotransformation of CIT enantiomers. These results confirm that the use of cDNA expressed CYP isozymes is a potent tool for the measurement of kinetic constants and help to predict clearance modifications of CIT enantiomers, especially in poor metabolizers of mephenytoin (with a CYP2C19 deficiency) or patients comedicated with potent CYP2C19 or 3A4 inhibitor(s). For instance, fluvoxamine (100 microM) inhibits CIT N-demethylation by 64% in microsomes.
Keywords
*Aryl Hydrocarbon Hydroxylases B-Lymphocytes Cell Line Citalopram/analogs & derivatives/*metabolism/pharmacology Cytochrome P-450 CYP2D6/*metabolism Cytochrome P-450 Enzyme System/*metabolism Humans Kinetics Microsomes, Liver/*enzymology Mixed Function Oxygenases/*metabolism Recombinant Proteins/metabolism Stereoisomerism Transfection
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Web of science
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25/01/2008 8:47
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20/08/2019 15:25
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