A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine.
Article Details
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Evert B, Griese EU, Eichelbaum M
A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine.
Naunyn Schmiedebergs Arch Pharmacol. 1994 Oct;350(4):434-9.
- PubMed ID
- 7845481 [ View in PubMed]
- Abstract
The sparteine/debrisoquine polymorphism is a clinically important genetic deficiency of cytochrome P4502D6-catalyzed oxidative drug metabolism. 5-10% of Caucasians designated as poor metabolizers have a severely impaired capacity to metabolize more than 30 therapeutically used drugs. Genotyping of a random Caucasian population for the known cytochrome P4502D6 mutations A, B and D which are associated with the poor metabolizer phenotype has revealed a substantial number of misclassified poor metabolizers indicating the existence of one or more unknown mutations which cannot be identified with the currently available genotyping assays. Therefore we have cloned and sequenced one nonfunctional cytochrome P4502D6 allele of a misclassified poor metabolizer and could identify a single missense mutation designated E mutation at position 3023(A-C) in exon 6. Direct sequencing analysis, FokI restriction analysis and a newly developed allele-specific polymerase chain reaction assay were applied to analyze for this mutation in a population study. Three out of 97 randomly selected Caucasians were carriers of this mutation and thus the E allele has a frequency of 1.5% (confidence interval95% = 0.33 - 4.54%). Since only 2 out of 4 misclassified poor metabolizers carried the E mutation, additional unknown mutant alleles must exist. Computer modelling suggests that the E mutation, which results in a histidine to proline exchange in position 324 of the protein, may cause an alteration of the 3D structure of CYP2D6 in close vicinity to the active site thereby leading to total loss of enzyme function.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Cytochrome P450 2D6 P10635 Details - Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Metoprolol Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
ADR Inferred Increased risk of slow heart rate (bradycardia) Details Venlafaxine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Codeine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Amitriptyline Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Imipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Dextromethorphan Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements Details Nortriptyline Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Tamoxifen Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor response to drug treatment, shorter time to relapse Details Desipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Clomipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Atomoxetine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*7 Not Available - 2935A>C (rs5030867)
Effect Inferred Poor drug metabolizer, increased side effects. Details