A natural variant of the heme-binding signature (R441C) resulting in complete loss of function of CYP2D6.
Article Details
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Klein K, Tatzel S, Raimundo S, Saussele T, Hustert E, Pleiss J, Eichelbaum M, Zanger UM
A natural variant of the heme-binding signature (R441C) resulting in complete loss of function of CYP2D6.
Drug Metab Dispos. 2007 Aug;35(8):1247-50. Epub 2007 Apr 25.
- PubMed ID
- 17460029 [ View in PubMed]
- Abstract
A new variant allele CYP2D6*62 (g.4044C>T; R441C) of the drug-metabolizing cytochrome P450 (P450) CYP2D6 was identified in a person with reduced sparteine oxidation phenotype, which was unexpected based on a genetic CYP2D6*1A/*41 background. The recombinantly expressed variant protein had no activity toward propafenone as a result of missing heme incorporation. Sequence alignment revealed that the positively charged R441 residue is part of the heme-binding signature but not strictly conserved among all the P450s. A compilation of described P450 monooxygenase variants revealed that other enzymes can functionally tolerate even nonconservative amino acid changes at the corresponding position (i.e., the invariant cysteine 2). This suggests that heme binding in mammalian P450s depends not only on the integrity of the heme-binding signature but also on other family- and subfamily-specific sequence determinants.
DrugBank Data that Cites this Article
- 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*62 Not Available - 4044C>T
ADR Inferred Increased risk of slow heart rate (bradycardia) Details Venlafaxine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Codeine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements Details Amitriptyline Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Imipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Dextromethorphan Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements Details Nortriptyline Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Tamoxifen Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor response to drug treatment, shorter time to relapse Details Desipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Clomipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Atomoxetine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*62 Not Available - 4044C>T
Effect Inferred Poor drug metabolizer, increased side effects. Details