A natural variant of the heme-binding signature (R441C) resulting in complete loss of function of CYP2D6.

Article Details

Citation

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
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
MetoprololCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
ADR InferredIncreased risk of slow heart rate (bradycardia)Details
VenlafaxineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirements, nausea, vomiting and diarrheaDetails
CodeineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
AmitriptylineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
ImipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
DextromethorphanCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
NortriptylineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
TamoxifenCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor response to drug treatment, shorter time to relapseDetails
DesipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
ClomipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
AtomoxetineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*62Not Available
  • 4044C>T
Effect InferredPoor drug metabolizer, increased side effects.Details