Ultrarapid metabolism of sparteine: Frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction

Lise Bathum*, Inger Johansson, Magnus Ingelman-Sundberg, Mogens Hørder, Kim Brøsen

*Kontaktforfatter for dette arbejde

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Resumé

CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes, In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8%, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.

OriginalsprogEngelsk
TidsskriftPharmacogenetics
Vol/bind8
Udgave nummer2
Sider (fra-til)119-123
Antal sider5
ISSN0960-314X
StatusUdgivet - 30. maj 1998

Fingeraftryk

Cytochrome P-450 CYP2D6
Restriction Fragment Length Polymorphisms
Polymerase Chain Reaction
Population
Gene Duplication
Control Groups
Enzymes
Alleles

Citer dette

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title = "Ultrarapid metabolism of sparteine: Frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction",
abstract = "CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes, In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8{\%}, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.",
keywords = "Cytochrome P450, Drug metabolism, Gene duplication, Long-PCR, Ultrarapid metabolism",
author = "Lise Bathum and Inger Johansson and Magnus Ingelman-Sundberg and Mogens H{\o}rder and Kim Br{\o}sen",
year = "1998",
month = "5",
day = "30",
language = "English",
volume = "8",
pages = "119--123",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
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Ultrarapid metabolism of sparteine : Frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction. / Bathum, Lise; Johansson, Inger; Ingelman-Sundberg, Magnus; Hørder, Mogens; Brøsen, Kim.

I: Pharmacogenetics, Bind 8, Nr. 2, 30.05.1998, s. 119-123.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Ultrarapid metabolism of sparteine

T2 - Frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction

AU - Bathum, Lise

AU - Johansson, Inger

AU - Ingelman-Sundberg, Magnus

AU - Hørder, Mogens

AU - Brøsen, Kim

PY - 1998/5/30

Y1 - 1998/5/30

N2 - CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes, In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8%, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.

AB - CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes, In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8%, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.

KW - Cytochrome P450

KW - Drug metabolism

KW - Gene duplication

KW - Long-PCR

KW - Ultrarapid metabolism

UR - http://www.scopus.com/inward/record.url?scp=0031960328&partnerID=8YFLogxK

M3 - Journal article

C2 - 10022749

AN - SCOPUS:0031960328

VL - 8

SP - 119

EP - 123

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 2

ER -