Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population*

Agúndez, José A. G.; Ledesma, María C.; Ladero, José M.; Benı́tez, Julio

doi:10.1016/0009-9236(95)90151-5

Cited by 164 publications

(58 citation statements)

References 19 publications

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“…Of the 360 volunteers, 30 (8.3%) were found to carry a duplicated functional CYP2D6 gene and were thus classified as UM. The results indicate that the prevalence of this allelic variant in the Southern Italian (Sicilian) population is similar to that in a Spanish population [22,23] . This is consistent with the more frequent distribution of CYP2D6 gene duplication in the Mediterranean area compared to Northern Europe and may be indicative of a north-south gradient of the frequency within Europe.…”

Section: Cyp2c9 Cyp2c19 and Cyp2d6supporting

confidence: 64%

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Serpe

Canaparo

Scordo

et al. 2014

Drug Metabolism and Personalized Therapy

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: Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 ( CYP ) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.

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Section: Cyp2c9 Cyp2c19 and Cyp2d6supporting

confidence: 64%

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Serpe

Canaparo

Scordo

et al. 2014

Drug Metabolism and Personalized Therapy

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“…In addition, a intake of a single dose of the probe drugs debrisoquine or 42 kb XbaI allele with two copies of the CYP2D6 gene as well sparteine with subsequent determination of the ratio between as one copy of each of the pseudogenes CYP2D8 and the urinary recovery of the drug and the metabolite. In Cau-CYP2D7 has been described [12][13][14]. The duplicated casian populations, there is a large variation in the metabolic CYP2D6 genes are usually functional, and the 42 kb allele ratio (MR) of the probe drugs, leading to the classification of has therefore been associated with the UM phenotype.…”

Section: Abstract Up To 7% Of Caucasians May Demonstrate Ultrarapidmentioning

confidence: 99%

“…Here we describe the Up to 7% of Caucasians are ultrarapid metabolizers (UMs) genomic organization of the duplicated CYP2D6 genes in the 42 of debrisoquine due to inheritance of alleles with duplication kbXbalallele. We postulate that this duplication originates from of functional CYP2D6 genes [12][13][14]. The mechanism by a homologous, unequal cross-over event which involved two 29 kb which this duplication has occurred is not known.…”

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confidence: 99%

Ultrarapid metabolizers of debrisoquine: Characterization and PCR‐based detection of alleles with duplication of the CYP2D6 gene

et al. 1996

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Up to 7% of Caucasians may demonstrate ultrarapidassays for the CYP2D6*3, CYP2D6*4, CYP2D6*5, CYmetabolism of debrisoquine due to inheritance of alleles with P2D6*6 and CYP2D6*7 null alleles [4--11]. duplicated functional CYP2D6 genes. Here we describe the Up to 7% of Caucasians are ultrarapid metabolizers (UMs) genomic organization of the duplicated CYP2D6 genes in the 42 of debrisoquine due to inheritance of alleles with duplication kbXbalallele. We postulate that this duplication originates from of functional CYP2D6 genes [12][13][14]. The mechanism by a homologous, unequal cross-over event which involved two 29 kb which this duplication has occurred is not known. When subXbaI wild-type alleles, and had break points within a 2.8 kb jected to standard doses of CYP2D6 substrates, UMs may direct repeat (CYP-REP) flanking the CYP2D6 gene. Moresuffer from therapeutic failure because of the very rapid metaover, we have designed two different PCR assays for detection of bolic conversion of the drugs [15,16]. Phenotyping with probe alleles with duplicated CYP2D6 genes. Both assays correctly drugs may be used to identify both PM and UM subjects. identified 29 out of 29 subjects positive for the 42 kb XbaI allele.However, the procedure is time-consuming and expensive, No false negative or false positive reactions were observed, and phenotype determination can b~ confounded by concomi- by a deletion of the entire CYP2D6 gene, and contains only CYP2D6 enzyme activity can be measured in vivo after oral the pseudogenes CYP2D8 and CYP2D7 [6,20]. In addition, a intake of a single dose of the probe drugs debrisoquine or 42 kb XbaI allele with two copies of the CYP2D6 gene as well sparteine with subsequent determination of the ratio between as one copy of each of the pseudogenes CYP2D8 and the urinary recovery of the drug and the metabolite. In Cau-CYP2D7 has been described [12][13][14]. The duplicated casian populations, there is a large variation in the metabolic CYP2D6 genes are usually functional, and the 42 kb allele ratio (MR) of the probe drugs, leading to the classification of has therefore been associated with the UM phenotype. three different phenotypes: poor, extensive and ultrarapid meWe have recently demonstrated the presence of two large tabolizers, direct repeats (CYP-REP) flanking the CYP2D6 locus [11,20]. 5-10% of Caucasians are classified as poor metabolizersThe break points of the CYP2D6*5 gene deletion allele are (PMs) of debrisoquine due to inheritance of two mutant present within the 2.8 kb CYP-REP regions, indicating that CYP2D6 null alleles [2,3]. With some CYP2D6 drug subthe deletion has occurred by homologous, unequal recombistrates, PM subjects may develop toxic plasma concentrations nation [20]. We also proposed that alleles with duplication of and adverse reactions at the standard recommended dose due CYP2D6 could be explained as a reciprocal of the deletion to impaired metabolism. Most of the non-functional CYP2D6 event, involving the same CYP-REP units. alleles have been described and ch...

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“…Recent results from several laboratories have demonstrated that a limited CYP2D6 allele set may predict the vast majority of Caucasian individuals lacking CYP2D6 enzyme activity with close to 100% accuracy (2)(3)(4)(5)(6)(7)(8). As more CYP2D6 null and reduced activity alleles have been discovered in various populations, the ability to account for more subtle variations in CYP2D6 enzyme activity has improved.…”

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confidence: 99%

Comparison of Two CYP2D6 Genotyping Methods and Assessment of Genotype-Phenotype Relationships

et al. 2003

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Background: There have been no published reports comparing the CYP450 GeneChip ® microarray assay with more standard methods of genetic testing. Methods: We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay. Five of the CYP2D6 alleles (*3, *4, *6, *7, and *9) were tested by both AS-PCR and the CYP450 GeneChip assay in an independent and blinded fashion in 232 of the 236 healthy volunteers. The combined CYP2D6 genotype from both methods was used to divide the population into four subgroups, poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs), based on their relative function and ability to express the CYP2D6 gene. The urinary elimination of dextromethorphan was assessed in each of these CYP2D6 subgroups.

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Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population*

Cited by 164 publications

References 19 publications

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Ultrarapid metabolizers of debrisoquine: Characterization and PCR‐based detection of alleles with duplication of the CYP2D6 gene

Comparison of Two CYP2D6 Genotyping Methods and Assessment of Genotype-Phenotype Relationships

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