Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype.

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Daly AK, Fairbrother KS, Andreassen OA, London SJ, Idle JR, Steen VM

Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype.

Pharmacogenetics. 1996 Aug;6(4):319-28.

PubMed ID

8873218 [ View in PubMed

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Abstract

The majority of humans deficient in the cytochrome P450 CYP2D6 enzyme, so-called poor metabolizers (PMs), can now be identified by genotyping for several different PM-associated mutations. However, additional null alleles remain to be identified as demonstrated by subjects with the PM phenotype in the absence of a corresponding genotype. The rare 11 kb band on Xba I RFLP analysis, which is distinct from the 13 kb CYP2D6D (CYP2D6*5) allele, has been proposed to constitute such a unique non-functional allele. Here we demonstrate that the 11 kb band represents at least two different nine exon CYP2D7P/CYP2D6 hybrids generated by large deletions in the CYP2D gene cluster due to unequal cross-over or looping-out mechanisms. The total allele frequency was approximately 0.001-0.01 in European and North American Caucasians. The most common variant (CYP2D6*16) had breakpoints lying between the end of exon 7 and the start of exon 9 of the respective genes. The "CYP2D7-like' part of the gene was most homologous to the previously described CYP2D7AP and CYP2D7 (44/11.5) sequences. The other chimeric allele consisted of exon 1 of CYP2D7 and exons 2-9 from CYP2D6, and may be similar to a hybrid gene termed CYP2D6*13 recently described in a French individual. Two different routine PCR assays were developed for rapid and sensitive detection of these alleles, namely amplification of a 8 kb fragment from both CYP2D6*13 and CYP2D6*16, together with a CYP2D6*16-specific method which gave a 1.4 kb PCR product. The 8 kb assay for the CYP2D6*13 and CYP2D6*16 alleles also produced a 9.5 kb fragment in samples positive for the 13 kb CYP2D6*5 allele. Therefore, it is now possible to screen for the large CYP2D gene deletions by a single long PCR method.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Metoprolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	ADR Inferred	Increased risk of slow heart rate (bradycardia)	Details
Venlafaxine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Amitriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Imipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Dextromethorphan	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Nortriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Tamoxifen	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor response to drug treatment, shorter time to relapse	Details
Desipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Clomipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Atomoxetine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, increased side effects.	Details