DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers

Panserat, Stéphane; Mura, Catherine; Gérard, Nathalie; Vincent‐Viry, Monique; Galteau, Marie‐Madeleine; Jacqz-Aigrain, Évelyne; Krishnamoorthy, R.

doi:10.1007/bf00201601

Cited by 27 publications

(12 citation statements)

References 27 publications

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“…The allele frequencies of CYP2D6 * 1 , CYP2D6 * 2, CYP2D6 * 5 , and CYP2D6 * 10 are 44.7, 17.0, 4.3, and 34.0%, respectively. There were several reports that the subjects who carried one copy of the CYP2D6 * 2 had significantly decreased CYP2D6 activity, 17,18 while multiple copies of CYP2D6 * 2 resulted in the increased activity of CYP2D6. 17–19 Therefore the subjects who had CYP2D6 * 2 mutation were excluded because the number of copies of CYP2D6 * 2 was not analyzed in this study.…”

Section: Resultsmentioning

confidence: 99%

“…There were several reports that the subjects who carried one copy of the CYP2D6 * 2 had significantly decreased CYP2D6 activity, 17,18 while multiple copies of CYP2D6 * 2 resulted in the increased activity of CYP2D6. 17–19 Therefore the subjects who had CYP2D6 * 2 mutation were excluded because the number of copies of CYP2D6 * 2 was not analyzed in this study. Further, the number of subjects who had CYP2D6 * 5 allele was so small that we got together the two genotype groups which carried CYP2D6 * 5 allele, and the analysis was performed among the four genotype groups.…”

Section: Resultsmentioning

confidence: 99%

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The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

Someya

Suzuki

Saito

et al. 1999

Psychiatry Clin Neurosci

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The value of haloperidol (HAL) in the treatment of schizophrenia and other psychiatric disorders has been well established. Its metabolism has been studied intensively. HAL is N-dealkylated to p-fluorobenzoylpropionic acid (FBPA) and to 4-(4-chlorophenyl) -4-hydroxypiperidene (CPHP), 1 reduction of the benzylic ketone produces reduced haloperidol (RHAL) by a cytosolic carbonyl reductase, 2 RHAL is reversely oxidated to HAL, 3 and HAL and RHAL undergo glucuronide conjugation. 4 Moreover, several other metabolic pathways of HAL are known, including formation of neurotoxic pyridinium metabolites by CYP3 A4.In vitro 3,5 and in vivo 6-8 studies suggested the involvement of CYP2D6 in HAL metabolism. Disposition of HAL is related to the polymorphic debrisoquine oxidation phenotype, 7 and the oxidation of RHAL to HAL is inhibited in vitro by quinidine, a potent inhibitor of CYP2D6, 3 although Young et al. have shown that quinidine does not affect the interconversion of HAL and RHAL. 9 CYP2D6 activity is reported in population studies to be bimodally distributed. Subjects who lack CYP2D6 activity are referred to as poor metabolizers, and they can be detected by screening for the specific alleles, Psychiatry and Clinical Neurosciences (1999) AbstractWe investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean ± SD, 0.66 ± 0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean ± SD, 0.36 ± 0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean ± SD, 0.48 ± 0.32, n = 47). The analysis was performed among the four genotype groups:CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

Someya

Suzuki

Saito

et al. 1999

Psychiatry Clin Neurosci

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“…In order to explore the molecular basis of the PM phenotype associated with the XbaI-9 kb mutant allele, systematic sequencing of all nine exons and exon-intron boundaries of the presumptively mutant CYP2D6 allele was carried out by PCR amplification using CYP2D6 gene specific primers [18]. For .kb/ kb .-Skb D7)…”

Section: Resultsmentioning

confidence: 99%

“…A detailed description of the polymorphic profiles for the BamHl and NcoI enzymes and the corresponding genotypes derived from these data are depicted in Figure 1 and Figure 3a. Nucleotide sequencing of the CYP2D6 exons and exon-intron junctions was carried out as described earlier [18].…”

Section: Subjects Phenotypes and Genotypesmentioning

confidence: 99%

An unequal cross‐over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

Panserat

Mura

Gérard

et al. 1995

Brit J Clinical Pharma

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1. The study of the CYP2D genotype and phenotype of a Caucasian family revealed that a XbaI‐9 kb allele was associated with the poor metabolizer phenotype. 2. A Polymerase Chain Reaction (PCR)‐based assay showed that the previously described mutations D6A and D6B are not associated with the XbaI‐9 kb allele. 3. To explore the molecular basis of the poor metabolizer phenotype associated with the XbaI‐9 kb allele, complete sequencing of the nine exons and intron‐exon boundaries of the CYP2D6 gene was undertaken after amplification by PCR. 4. All the exons were successfully amplified using CYP2D6 gene‐specific primers except exon 1 which required a combination of CYP2D7 gene‐specific 5' primer and a CYP2D6 gene‐specific 3' primer. 5. Sequence data derived from this amplified product revealed that the XbaI‐9 kb allele corresponds to a novel rearrangement of the locus. This involved a deletion of an approximately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2D6 3' gene. 6. The chimeric gene is non‐functional presumably due to an insertion in exon 1 (characteristic of the exon 1 of the CYP2D7 gene) which causes a shift in the reading frame with premature termination of translation.

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“…In the first characterization of the CYP2D6 allele *41, this variant was recognized based on the presence of the 2850C>T SNP, and the lack of −1584C>G, distinguishing it from allele *2A 54,55. Later studies by Raimundo et al42 and Toscano et al43 have proven that the aberrant splicing of this variant is due to a single G>A transition located at 2988 nt in the gene.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic testing revisited: 5′nuclease real-time polymerase chain reaction test panels for genotyping <em>CYP2D6 </em>and <em>CYP2C19</em>

Larsen

Rasmussen

2017

PGPM

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Due to their involvement in the metabolization of commonly prescribed psychopharmaceutical drugs, the cytochrome oxidase genes CYP2D6 and CYP2C19 are extensive targets for pharmacogenetic testing. The existence of common allelic variants allows the prediction of a metabolic phenotype based on a genotype result, hereby supplying a clinical tool for optimizing prescription and minimizing adverse effects. In this study, we present the development of two 5′ nuclease real-time polymerase chain reaction (PCR) test panels, capable of detecting eight of the most clinically relevant alleles of the CYP2D6 gene (*2, *3, *4, *6, *9, *10, 17, *41) and the three most common nonfunctional alleles of CYP2C19 (*2, *3, *4). The assays have been thoroughly validated using a large collection of reference samples, by parallel testing and by DNA sequencing. The reanalysis of reference samples provided the calculation of the frequency of the CYP2D6*4K allele in a population, not previously reported. Furthermore, original test results from CYP2D6*41, generated based on the presence of the 2850T and the lack of the −1584G single-nucleotide polymorphism (SNP), were compared with genotyping based on the current acknowledged founder SNP 2988G of this allele. These results indicate that up to 17.7% of the patients originally tested as carriers of the CYP2D6*41 allele may have had an incorrect phenotypic result assigned. The two 5′ nuclease real-time PCR test panels have subsequently been optimized for use in the clinical laboratory, using a standard real-time PCR instrument and software.

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DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers

Cited by 27 publications

References 27 publications

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

An unequal cross‐over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

Pharmacogenetic testing revisited: 5′nuclease real-time polymerase chain reaction test panels for genotyping <em>CYP2D6 </em>and <em>CYP2C19</em>

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DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers

Cited by 27 publications

References 27 publications

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

An unequal cross‐over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

Pharmacogenetic testing revisited: 5&prime;nuclease real-time polymerase chain reaction test panels for genotyping <em>CYP2D6 </em>and <em>CYP2C19</em>

Contact Info

Product

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Pharmacogenetic testing revisited: 5′nuclease real-time polymerase chain reaction test panels for genotyping <em>CYP2D6 </em>and <em>CYP2C19</em>