Source:http://linkedlifedata.com/resource/pubmed/id/11752104
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2001-12-25
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| pubmed:abstractText |
This work evaluated the kinetic behavior of fluoxetine O-dealkylation in human liver microsomes from different CYP2C19 genotypes and identified the isoenzymes of cytochrome P450 involved in this metabolic pathway. The kinetics of the rho-trifluoromethylphenol (TFMP) formation from fluoxetine was determined in human liver microsomes from three homozygous (wt/wt) and three heterozygous (wt/m1) extensive metabolizers (EMs) and three poor metabolizers (PMs) with m1 mutation (m1/m1) with respect to CYP2C19. The formation rate of TFMP was determined by gas chromatograph with electron-capture detection. The kinetics of TFMP formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equation for liver microsomes from CYP2C19 EMs and PMs, respectively. The mean intrinsic clearance (V(max)/K(m)) for the high- and low-affinity component was 25.2 microl/min/nmol and 3.8 microl/min/nmol of cytochrome P450 in the homozygous EMs microsomes and 12.8 microl/min/nmol and 2.9 microl/min/nmol of cytochrome P450 in the heterozygous EMs microsomes, respectively. Omeprazole (a CYP2C19 substrate) at a high concentration and triacetyloleandomycin (a selective inhibitor of CYP3A4) substantially inhibited O-dealkylation of fluoxetine. Furthermore, fluoxetine O-dealkylation was correlated significantly with S-mephenytoin 4'-hydroxylation at a low substrate concentration and midazolam 1'-hydroxylation at a high substrate concentration in liver microsomes of 11 Chinese individuals, respectively. Moreover, there were obvious differences in the O-dealkylation of fluoxetine in liver microsomes from different CYP2C19 genotypes and in microsomal fractions of different human-expressed lymphoblast P450s. The results demonstrated that polymorphic CYP2C19 and CYP3A4 enzymes were the major cytochrome P450 isoforms responsible for fluoxetine O-dealkylation, whereas CYP2C19 catalyzed the high-affinity O-dealkylation of fluoxetine, and its contribution to this metabolic reaction was gene dose-dependent.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases,
http://linkedlifedata.com/resource/pubmed/chemical/CYP2C19 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP3A,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fluoxetine,
http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Uptake Inhibitors
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jan
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| pubmed:issn |
0022-3565
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
300
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
105-11
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| pubmed:dateRevised |
2008-11-21
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| pubmed:meshHeading |
pubmed-meshheading:11752104-Algorithms,
pubmed-meshheading:11752104-Aryl Hydrocarbon Hydroxylases,
pubmed-meshheading:11752104-Chromatography, Gas,
pubmed-meshheading:11752104-Cytochrome P-450 CYP3A,
pubmed-meshheading:11752104-Cytochrome P-450 Enzyme System,
pubmed-meshheading:11752104-DNA, Complementary,
pubmed-meshheading:11752104-Dealkylation,
pubmed-meshheading:11752104-Electrochemistry,
pubmed-meshheading:11752104-Enzyme Inhibitors,
pubmed-meshheading:11752104-Fluoxetine,
pubmed-meshheading:11752104-Gene Dosage,
pubmed-meshheading:11752104-Genotype,
pubmed-meshheading:11752104-Humans,
pubmed-meshheading:11752104-Kinetics,
pubmed-meshheading:11752104-Microsomes, Liver,
pubmed-meshheading:11752104-Mixed Function Oxygenases,
pubmed-meshheading:11752104-Recombinant Proteins,
pubmed-meshheading:11752104-Serotonin Uptake Inhibitors
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| pubmed:year |
2002
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| pubmed:articleTitle |
O-Dealkylation of fluoxetine in relation to CYP2C19 gene dose and involvement of CYP3A4 in human liver microsomes.
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| pubmed:affiliation |
Pharmacogenetics Research Institute, Xiang-Ya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
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| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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