A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype

Marez, Delphine; Sabbagh, N; Legrand, M.; Lo-Guidice, Jean-Marc; Boone, Philip M.; Broly, Franck

doi:10.1097/00008571-199510000-00006

Cited by 37 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CYP2D6 * 10 alleles were detected using the method of Marez et al. [19]. Detection of alleles containing deleted genes ( CYP2D6 * 5 and * 16 ) or amplified genes ( CYP2D6 * 1xN , * 2xN and * 4xN ) was performed using PCR‐based assays [20, 21].…”

Section: Methodsmentioning

confidence: 99%

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

Davies

Coller

James

et al. 2005

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims CYP2D6 protein expression is determined by the number of functional CYP2D6alleles. It is also higher in individuals with at least one CYP2D6 * 2 allele. This study has investigated the effect of the number of functional CYP2D6 alleles and the influence of CYP2D6 * 2 alleles on plasma perhexiline concentrations in patients administered a standard loading regimen over 3 days. MethodsEighteen patients with myocardial ischaemia who were not taking any drugs known to inhibit CYP2D6 metabolism in vivo commenced treatment with 200 mg of perhexiline twice per day. On the fourth day, blood was drawn for genotyping and the measurement of trough plasma concentrations of perhexiline and its major metabolite, cis -OH-perhexiline. ResultsThe only genotypic CYP2D6 poor metabolizer had a trough plasma perhexiline concentration of 2.70 mg l − 1 and no detectable cis -OH-perhexiline. The mean ± SD trough plasma perhexiline concentration in patients with one functional allele was significantly higher (0.63 ± 0.31 mg l − 1 , n = 8, P = 0.05) than in patients with two functional alleles (0.37 ± 0.17 mg l − 1 , n = 9). Conversely, the mean metabolic ratio was significantly lower in patients with one functional allele (2.90 ± 1.76, P < 0.01) compared with patients with two functional alleles (6.52 ± 3.26). Patients with at least one CYP2D6 * 2 allele had a lower plasma perhexiline concentration (0.20 ± 0.09 mg l − 1 , n = 5, P < 0.001) and a higher metabolic ratio (7.86 ± 2.51, P < 0.01) than the non-poor metabolizer patients with no CYP2D6 * 2 alleles (0.62 ± 0.23 mg l − 1 and 3.55 ± 2.54, respectively, n = 12). ConclusionPatients with only one functional allele and not CYP2D6 * 2 have diminished CYP2D6 metabolic capacity for perhexiline.

show abstract

Section: Methodsmentioning

confidence: 99%

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

Davies

Coller

James

et al. 2005

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Venous blood (7 ml) was obtained from each of the 162 subjects, and deoxyribonucleic acid (DNA) was isolated from peripheral leucocytes using an extraction kit (Genomix, Talent, Trieste, Italy). The CYP2D6 wild‐type gene and the 11 mutated alleles were identified by a polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP), by mismatch‐or by long‐PCR analysis directed against one or more relevant mutated sites using allele‐specific primers [4–11].…”

Section: Methodsmentioning

confidence: 99%

Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O‐demethylation in different CYP2D6 genotypes

Kubota

Yamaura

Ohkawa³

et al. 2000

Brit J Clinical Pharma

145

111

View full text Add to dashboard Cite

Aims To determine the frequencies of 11 CYP2D6 mutant alleles (CYP2D6*2,*3,*4,*5,*8,*10,*11,*12,*14,*17 and *18), and their relation to the metabolic capacity of CYP2D6 in Japanese subjects. Methods One hundred and sixty‐two unrelated healthy Japanese subjects were genotyped with the polymerase chain reaction amplification method and 35 subjects were phenotyped with dextromethorphan. Results The frequencies of CYP2D6*2,*5, *10 and *14 were 12.9, 6.2, 38.6 and 2.2% in our Japanese subjects, respectively. CYP2D6*3, *4, *8, *11, *12, *17 and *18 were not detected. The mean log metabolic ratio of dextromethorphan in subjects with genotypes predicting intermediate metabolizers was significantly greater than that of heterozygotes for functional and defective alleles. Conclusions CYP2D6*5 and CYP2D6*14 are the major defective alleles found in Japanese subjects. In addition, CYP2D6*10 may play a more important role than previously thought for the treatment of Japanese patients with drugs metabolized by CYP2D6.

show abstract

“…In pharmacogenomics, high throughput sequencing may be very useful as changes in gene expression or splicing are important for drug disposition (Marez et al, 1995; Chou et al, 2001; Kuehl et al, 2001; Pitarque et al, 2001; Lang et al, 2004; Menard et al, 2011). However, the high cost and complexity of data analyses delay the implementation of this approach.…”

Section: How Can High Throughput Sequencing Be Useful In Pharmacogenomentioning

confidence: 99%

Pharmacogenomics: What is Next?

Iulio

Rotger

2012

Front. Pharmacol.

View full text Add to dashboard Cite

Pharmacogenomics is moving from a candidate gene strategy to large scale approaches. This is in line with the new paradigm of linking a trait to (a) pathway(s) rather than to single genes. In addition, breakthroughs in genomics offer a non-a priori assessment of implicated genes, expanding the possibilities in pharmacogenomics research. In this review, we discuss the pros and cons of new concepts in study design and on high throughput approaches to be implemented in the near future.

show abstract

A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype

Cited by 37 publications

References 0 publications

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O‐demethylation in different CYP2D6 genotypes

Pharmacogenomics: What is Next?

Contact Info

Product

Resources

About

A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype

Cited by 37 publications

References 0 publications

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O‐demethylation in different CYP2D6 genotypes

Pharmacogenomics: What is Next?

Contact Info

Product

Resources

About

Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O‐demethylation in different CYP2D6 genotypes