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GENETIC POLYMORPHISMS OF CYTOCHROME P450 (CYP) 2D6 |
Allele |
Population
|
Single Nucleotide
Polymorphism
|
Location
|
CYP2D6
Activity
|
Notes
|
CYP2D6*1
|
General Population |
Wild-type; 5,139bp
|
22q13.1
|
normal
|
Extensive metabolizer |
CYP2D6*2xn |
Ethiopians/Saudi
Arabian 10-16%
Caucasians 1-5%
Asians 0-2%
|
Gene duplication
C2983T (R296C)
G4268C (S486T)
|
Exon 6
Exon 9
|
↑
|
Ultra-rapid or extensive
metabolizer
|
CYP2D6*3 |
Asians 0%
|
1-bp deletion 2637A
or (aka., 2549A)
|
Exon 5
|
absent
|
Poor metabolizer due
to frame shift mutation
|
CYP2D6*4 |
African Americans 2%
|
G1934A |
Junction
of Intron 3
& Exon 4
|
absent |
Poor to no metabolic
activity due to a
splicing defect |
CYP2D6*5 |
Caucasians 0.04%
African Americans 4%
|
11.5-kb deletion
on gene
|
On allele |
absent
|
No 2D6 enzyme
present in liver
|
CYP2D6*6
|
Caucasians 1.8%
|
Deletion of T-1795
causing a premature
stop codon
|
Exon 3
|
absent |
Poor metabolizer non-
functioning variant |
CYP2D6*9
|
NR |
AGA deletion at
2613-2615 (K281)
|
-
|
↓/↔
|
Poor metabolizer
|
CYP2D6*10
|
Asians 39-51%
African American 6%
Caucasians 1-2%
|
C188T; also seen as
C100T (P34S)
|
Exon 1
|
↓
|
Intermediate metabolizer
|
CYP2D6*14
|
Asian 2.2%
|
P34S
G169R
R296C
S486T
|
Exon 3
|
absent
|
Poor metabolizer; non-
functional enzyme
|
CYP2D6*17
|
African Americans
20-35%
|
C111T (T107I)
C2938T (R296S)
G4268C (S486T)
|
Intron 1
|
↓
|
Altered affinity for
substrates of 2D6
|
CYP2D6*29
|
Black Africans 20%
|
G3183A
|
-
|
↓
|
Poor metabolizer |
CYP2D6*41
|
Caucasians 8-10%
African American 11%
Japanese 2.6%
|
G2988A
|
Intron 6
|
↓
|
Intermediate metabolizer
due to aberrant splicing
|
|
The letters before and after the numbers represent the single nucleotides that make up the DNA sequence and codons to code for an
amino acid (A = adenine, C = cytosine, G = guanine, T = thymine).
Amino acids represented:(C = cysteine, G = glycine, K = lysine, P =
proline, R = arginine, S = serine, T = threonine, V = valine). NR = not reported.
References:
-
Gough
AC, Smith C A, Howell S M et al. Localization of the CYP2D gene locus
to human chromosome 22q13.1 by polymerase chain reaction, in situ
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Kimura S, Umeno M, Skoda R C et al. The human debrisoquine 4-hydroxylase
(CYP2D) locus: sequence and identification of the polymorphic CYP2D6
gene, a related gene, and a pseudogene. Am J Hum Genet 1989;45:889-904. PubMed
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Griese EU, Asante-Poku S, Ofori-Adjei D et al. Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics 1999;9:715-23. PubMed
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Kubota T, Yamaura Y, Ohkawa N et al.
Frequencies of CYP2D6 mutant alleles in a normal Japanese population
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Johansson
I, Lundqvist E, Bertilsson L et al. Inherited amplification of an
active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid
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Gough AC, Miles JS, Spurr NK et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990;347:773-776. PubMed
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Hanioka
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intron 3 of a mutant CYP2D6 allele results in an aberrant 3-prime splice
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Gaedigk
A, Blum M, Gaedigk R et al. Deletion of the entire cytochrome P450
CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers
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Nelson
DR, Koymans L, Kamataki T et al. Cytochrome P450 superfamily: update on
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Steen VM, Molven A, Aarskog NK et al.
Homologous unequal cross-over involving a 2.8 kb direct repeat as a
mechanism for the generation of allelic variants of the human cytochrome
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Saxena
R, Shaw GL, Relling MV et al. Identification of a new variant CYP2D6
allele with a single base deletion in exon 3 and its association with
the poor metabolizer phenotype. Hum Molec Genet 1994;3:923-926. PubMed
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Tyndale R, Aoyama T, Broly F et al.
Identification of a new variant CYP2D6 allele lacking the codon
encoding Lys-281: possible association with the poor metabolizer
phenotype. Pharmacogenetics 1991;1:26-32. PubMed
-
Kagimoto
M, Heim M, Kagimoto K et al. Multiple mutations of the human cytochrome
P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: study of
the functional significance of individual mutations by expression of
chimeric genes. J Biol Chem 1990;265:17209-17214. PubMed
-
Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in chinese. Drug Metab Dispos 1999;27:385-8. PubMed
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Masimirembwa C, Persson I, Bertilsson L et al.
A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black
African population: association with diminished debrisoquine
hydroxylase activity. Br J Clin Pharmacol 1996;42:713-9. PubMed
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Wennerholm A, Johansson I, Hidestrand M et al. Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity. Pharmacogenetics 2001;11:417-27. PubMed
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Ikenaga Y, Fukuda T, Fukuda K et al.
The frequency of candidate alleles for CYP2D6 genotyping in the
Japanese population with an additional respect to the -1584C to G
substitution. Drug Metab Pharmacokinet 2005;20:113-6. PubMed
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Raimundo S, Toscano C, Klein K et al. A novel intronic mutation, 2988G>A, with predictivity for impaired function of cytochrome P450 2D6 in white subjects. Clin Pharmacol Ther 2004;76:128-38. PubMed
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