Source:http://linkedlifedata.com/resource/pubmed/id/11505218
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
6
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pubmed:dateCreated |
2001-8-15
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pubmed:abstractText |
CYP2D6 is involved in the metabolism of several classes of drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors and various amphetamines. CYP2D6*10 is an allelic variant, producing an enzyme with Pro34Ser and Ser486Thr amino acid substitutions. Approximately 75% of Asians possess the *10 allele. We sought to further characterize CYP2D6.10 catalytically in vitro in a baculovirus expression system using various substrates and inhibitors, in comparison to CYP2D6.1 (wild-type). Using dextromethorphan (DEX), P-methoxyamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)3,4-methylenedioxymethamphetamine (MDMA), the ratios of intrinsic clearance (Vmax/Km) of *1 to *10 were 50, 34, 22 and 123, respectively. The CYP2D6 substrates amitriptyline, and (+) and (-) methamphetamine (MAMP) are both p-hydroxylated and N-demethylated (NDM). The intrinsic clearance *1/*10 ratios were 42, 30 and 67 for the p-hydroxylation; and 60, 120 and 157 for the NDM, respectively, illustrating chemical pathway and enantiomeric selectivity for MAMP. It was apparent that (+) and (-) MAMP NDM and MDMA demethylenation were most significantly different in CYP2D6.10. Using DEX as the substrate, the ratios of Ki(*10)/Ki(*1) for inhibitors were: budipine (1.3), sparteine (1.6), debrisoquine (8.1), fluoxetine (16), norfluoxetine (30), paroxetine (14), MDMA (21) and MMDA-2 (7.1), indicating that CYP2D6.10 shows drug-specific altered susceptibility to inhibition. Taken together, these data suggest that CYP2D6*10/*10 individuals may be expected to require different drug doses; and show altered susceptibility to toxicity, interaction risk and, in the case of the amphetamines, drug dependence and toxicity compared to CYP2D6*1/*1 individuals.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-Methyl-4-phenyl-1,2,3,6-tetrahydro...,
http://linkedlifedata.com/resource/pubmed/chemical/Amitriptyline,
http://linkedlifedata.com/resource/pubmed/chemical/Amphetamines,
http://linkedlifedata.com/resource/pubmed/chemical/Antidepressive Agents, Tricyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP2D6,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Uptake Inhibitors
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0960-314X
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
11
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
477-87
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:11505218-1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine,
pubmed-meshheading:11505218-Amitriptyline,
pubmed-meshheading:11505218-Amphetamines,
pubmed-meshheading:11505218-Antidepressive Agents, Tricyclic,
pubmed-meshheading:11505218-Cytochrome P-450 CYP2D6,
pubmed-meshheading:11505218-Humans,
pubmed-meshheading:11505218-Isoenzymes,
pubmed-meshheading:11505218-Serotonin Uptake Inhibitors,
pubmed-meshheading:11505218-Substrate Specificity
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pubmed:year |
2001
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pubmed:articleTitle |
Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates.
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pubmed:affiliation |
Department of Pharmacology, University of Toronto, Toronto, Canada.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.
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