Localization of the CYP2D Gene Locus to Human Chromosome 22q13.1 by Polymerase Chain Reaction, in Situ Hybridization, and Linkage Analysis

Gough, A C; Smith, Christopher A.; Howell, Spencer M.; Wolf, Charles; Bryant, Stephen P.; Spurr, N.K.

doi:10.1006/geno.1993.1082

Cited by 53 publications

(24 citation statements)

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“…The CYP2D6 gene belongs to the CYP2 family and was mapped in human chromosome 22, band 22q13.1 (Gough et al, 1993). Enzyme CYP2D6 (debrisoquine-4-hydroxylase) metabolizes debrisoquine and at least 80 other drugs, like antidepressants, neuroleptics, many antiarrhythmics, and lipophilic β-blockers (Ayesh et al, 1984;Autrup, 2000;Bertilsson, 1995).…”

Section: Cyp2d6mentioning

confidence: 99%

Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility

Hatagima

2002

Cad. Saúde Pública

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Section: Cyp2d6mentioning

confidence: 99%

Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility

Hatagima

2002

Cad. Saúde Pública

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“…In the latter case it is interesting that blast cells were taken for the analysis and therefore the increase in PMs could be due to allele loss in the region of chromosome 22 where CYP2D6 maps. Recent studies have shown that this gene locus maps to within 4.2 cM of the platelet derived growth factor B chain gene whose oncogenic homologue is the sis oncogene (Gough et al 1993). …”

Section: Resultsmentioning

confidence: 99%

Molecular Genetics of the Human Cytochrome P450-Dependent Monooxygenases.

Wolf

Smith

et al. 1992

Tohoku J. Exp. Med.

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In this work, the role of genetic as well as environmental factors in determining cytochrome P450 isozyme levels in man have been studied. Simple DNA based assays for the identification of individuals nulled at the CYP2D6 locus are described and have been applied to investigate whether this gene defect is associated with altered cancer susceptibility. In contrast to literature reports, in no cancer type were poor metabolizers underrepresented, indeed in several cancers the mutant allele frequency was increased. A model using human tumours grown as xenografts is described that should help elucidate the factors which regulate P450 levels in man.human cytochrome P-450; cancer susceptibility ; mutant allele frequency ; CYP2D6 ; human tumor xenograft Cytochrome P450-dependent monooxygenases play a central role in the metabolism of drugs, chemical toxins and carcinogens. Individuality in the expression of P450 genes may therefore play an important role in individual susceptibility to diseases such as cancer. In this report we describe work on the environmental and genetic factors which regulate cytochrome P450 levels in man.The reactions catalyzed by these enzymes usually involves the incorporation of an atom of molecular oxygen into the substrate. In most cases this results in increased hydrophilicity and facilitates excretion. However, in certain cases this metabolic process results in the activation of the prodrug or procarcinogen converting it into its ultimate carcinogenic form. Possibly as a consequence of the central role of this enzyme system in detoxification, the cytochrome P450-dependent monooxygenases have evolved into a series of multigene families and in man there may be fifty or more distinct enzymes active in foreign compound metabolism (Nebert et al. 1991). Each of these forms exhibits its own unique Address for reprints ;

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“…This PM phenotype, inherited as an autosomal recessive trait, is due to the deficient activity of a cytochrome P450 enzyme, which is encoded by the CYP2D6 gene in man [5,6]. This gene is a member of a multigene cluster (CYP2D cluster) on chromosome 22ql3.1 [7,8]. The two other members of this cluster, namely CYP2D7 and CYP2D8P, exhibit high sequence homology to the functional CYP2D6 gene [9].…”

Section: Introductionmentioning

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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Localization of the CYP2D Gene Locus to Human Chromosome 22q13.1 by Polymerase Chain Reaction, in Situ Hybridization, and Linkage Analysis

Cited by 53 publications

References 0 publications

Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility

Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility

Molecular Genetics of the Human Cytochrome P450-Dependent Monooxygenases.

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

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