Analysis of the gene in relation to dextromethorphan -demethylation capacity in a Japanese population

Tateishi, Tetsuya; Chida, Michihiro; Ariyoshi, Noritaka; Mizorogi, Yoshihiro; Kamataki, Tetsuya; Kobayashi, Shinichi

doi:10.1016/s0009-9236(99)70077-9

Cited by 116 publications

(82 citation statements)

References 21 publications

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“…An IM phenotype is usually observed in populations harboring a combination of one CYP2D6 null allele and another allele with impaired expression and/or function, such as CYP2D6*10 (Zanger et al, 2004). The frequency of PMs is 5 to 10% in the Caucasian population and less than 1% in the Asian population (Sohn et al, 1991;Dahl et al, 1992;Tateishi et al, 1999). Among the variant alleles reported thus far, CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 account for approximately 97% of the PM alleles in the Caucasian population (Sachse et al, 1997).…”

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confidence: 99%

“…The catalytic properties of CYP2D6*10 and CYP2D6*2 have been studied extensively in vivo and in vitro using recombinant expression systems and reaction phenotyping. The frequency of CYP2D6*10 is relatively high in Asians, and individuals with an IM phenotype and with CYP2D6*10/*10 or CYP2D6*10/*null genotypes, respectively, exhibit lower catalytic activities toward typical CYP2D6 substrates such as dextromethorphan (Tateishi et al, 1999), metoprolol , and nortriptyline (Yue et al, 1998) than wild-type homozygous individuals. Subjects harboring CYP2D6*2/*2 exhibit metabolic activity similar to that of wild-type individuals for various substrates (Johansson et al, 1993; The purpose of this study was to investigate the functional characterization of the CYP2D6 variants identified in Japanese subjects.…”

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confidence: 99%

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Functional Characterization of 17CYP2D6Allelic Variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57)

Sakuyama¹,

Sasaki²,

Ujiie³

et al. 2008

Drug Metab Dispos

141

122

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Functional Characterization of 17CYP2D6Allelic Variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57)

Sakuyama¹,

Sasaki²,

Ujiie³

et al. 2008

Drug Metab Dispos

141

122

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“…Despite the very low frequency of poor metabolizers of CYP2D6 in Asian populations, these groups actually display lower mean CYP2D6 activity than Caucasians with the reference allele CYP2D6*1. This reduced activity is represented by a right shift in the metabolic ratio (parent/ metabolite ratio) for several CYP2D6 substrates, including debrisoquine (Kalow et al, 1980), sparteine (Droll et al, 1998), metoprolol (Horai et al, 1989), and dextromethorphan (Tateishi et al, 1999). This lower overall CYP2D6 activity has been attributed to the high frequency in the Asian populations of a reduced activity variant of CYP2D6, i.e., CYP2D6*10.…”

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confidence: 99%

Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17

Shen

He²,

Liu³

et al. 2007

Drug Metab Dispos

152

129

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ABSTRACT:Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNAexpressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.

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“…However, the remaining two alleles that are detected by the protocol and confer reduced levels of metabolism are common in African and Oriental Asian populations. In published datasets for Asian populations CYP2D6*10 ranges from 40% in Japanese [44] to 70% in Taiwanese Chinese [45]; CYP2D6*17 ranges in published datasets for African populations from 9% in Ethiopians [46] to 34% in Zimbabweans [47]. The genotypic information that the protocol provides can be used in conjunction with known CYP2D6 allele frequencies in different ethnic groups as a guide to deciding which other polymorphisms should be characterized, depending on whether a study is concerned with identifying URM or IM phenotypes.…”

Section: Resultsmentioning

confidence: 99%

High-throughput analysis of informative CYP2D6 compound haplotypes

et al. 2003

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We describe a high-throughput protocol for detecting key polymorphisms in the drug-metabolizing enzyme gene CYP2D6 and a number of linked microsatellites that is both fast and relatively inexpensive to perform. This approach employs GeneScan technology to enable a researcher to determine rapidly the status of seven simple nucleotide polymorphisms in CYP2D6 and also to assay repeat number variation at five closely linked dinucleotide microsatellite loci. The method requires only three PCRs and two GeneScan runs per sample. We anticipate that this will be of value to researchers in three different ways: (1) rapid discrimination of common CYP2D6 alleles, (2) high-resolution haplotyping for association studies involving chromosome 22q13.1 using microsatellite variation, and (3) generation of compound haplotypes for investigating the evolution of CYP2D6 variation. We also report compound haplotype frequencies for an Ashkenazi Jewish and a British sample. © 2003 Elsevier Science (USA). All rights reserved.Keywords: CYP2D6; Pharmacogenetics; Genotyping; Haplotype; Microsatellites; SNPs; Jews; British; Population; Variation It is now clear that much of the observed variation in drug efficacy and safety has a hereditary basis, arising from polymorphisms in genes coding for drug-metabolizing enzymes (DMEs). The frequency of DME alleles can vary greatly between different human populations, and this has implications for both medical and evolutionary studies. Consequently, there has been growing academic and commercial interest in the extent, nature, and causes of DME variation. However, it is currently unknown to what extent interpopulation variability is due to selection, drift, or other processes. Studies seeking to elucidate this have been held back by the absence of efficient low-cost high-throughput procedures for characterizing variability at the molecular level in and around DME loci. Ultimately, the identification of the molecular basis of pharmacogenetically relevant variation combined with the technology to screen individuals for the presence of specific alleles allows for the prediction of drug response and individualized treatment.Polymorphism in debrisoquine/sparteine oxidation is arguably the most highly studied pharmacogenetic trait. The DNA sequence encoding the enzyme has been localized to the 4.3-kb, nine-exon cytochrome P450 2D6 (CYP2D6) gene found at chromosome 22q13.1. To date more than 48 mutations and 53 alleles of CYP2D6 have been characterized in European populations [1]. The poor metabolizer (PM) phenotype follows an autosomal recessive pattern of inheritance [2]. An allele duplication consisting of multiple functional copies of CYP2D6 confers the ultrarapid metabolizer (URM) phenotype [3]. Individuals who demonstrate normal levels of CYP2D6 activity are referred to as extensive metabolizers. Intermediate metabolizers (IMs) typically produce lower than normal levels of functional enzyme.Medical interest in CYP2D6 polymorphism arises because the CYP2D6 enzyme has been found to process more t...

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Analysis of the gene in relation to dextromethorphan -demethylation capacity in a Japanese population

Cited by 116 publications

References 21 publications

Functional Characterization of 17CYP2D6Allelic Variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57)

Functional Characterization of 17CYP2D6Allelic Variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57)

Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17

High-throughput analysis of informative CYP2D6 compound haplotypes

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