Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17
| Autor: | Li Wang, Houfu Liu, Steven A. Wrighton, Bin Guo, Chuan Li, Hong Wu Shen, Minxia M. He |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
CYP2D6
Imipramine Pharmaceutical Science Nortriptyline Pharmacology Biology Atomoxetine Hydrochloride Hydroxylation digestive system Dextromethorphan Polymorphism Single Nucleotide chemistry.chemical_compound Cocaine Cytochrome P-450 CYP2D6 Inhibitors Fluoxetine Microsomes medicine Humans Allele Enzyme Inhibitors skin and connective tissue diseases Tramadol Genetics Molecular Structure Propylamines Codeine Thioridazine Bufuralol Null allele Quinidine Recombinant Proteins Debrisoquin Kinetics Debrisoquine chemistry Cytochrome P-450 CYP2D6 Ethanolamines Drug metabolism medicine.drug Atomoxetine hydrochloride |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 35(8) |
| ISSN: | 0090-9556 |
| Popis: | Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences. |
| Databáze: | OpenAIRE |
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