Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians

Droll, Kurt P.; Bruce-Mensah, K; Sv, Otton; Gaedigk, Andrea; Sellers, Edward M.; Tyndale, Rachel F.

doi:10.1097/00008571-199808000-00006

Cited by 79 publications

(48 citation statements)

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“…Furthermore, cases of genotype to phenotype discordance have been described in a number of studies, but remain unresolved. [17][18][19][20][21][22][23][24] The presence of the reduced function alleles CYP2D6*17 and *29 partially explain lower activity in Blacks, but additional nonfunctional alleles and alleles encoding protein with reduced enzymatic properties likely exist.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

et al. 2005

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Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6*41B, *45A and B and *46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A À692 TGTG deletion (CYP2D6*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6*45 and *46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.

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Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

et al. 2005

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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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“…High frequencies of *10 in Asian populations and *17 in African populations may influence phenotype patterns. [21,23] The frequency of CYP2D6*10 in the Korean population has been reported as 45.6%. [11] When applying a DM log MR value of ≥ -0.5 (the PM cutoff proposed by Schmid et al [15]), only *5/*5 was included in the data with a frequency of 0.8%.…”

Section: Discussionmentioning

confidence: 99%

Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms

Kim

Shin

2017

Transl Clin Pharmacol

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This study focused on the role of cytochrome P450 2D6 (CYP2D6) genotypes to predict phenotypes in the metabolism of dextromethorphan. CYP2D6 genotypes and metabolic ratios (MRs) of dextromethorphan were determined in 201 Koreans. Unsupervised clustering algorithms, hierarchical and k-means clustering analysis, and color visualizations of CYP2D6 activity were performed on a subset of 130 subjects. A total of 23 different genotypes were identified, five of which were observed in one subject. Phenotype classifications were based on the means, medians, and standard deviations of the log MR values for each genotype. Color visualization was used to display the mean and median of each genotype as different color intensities. Cutoff values were determined using receiver operating characteristic curves from the k-means analysis, and the data were validated in the remaining subset of 71 subjects. Using the two highest silhouette values, the selected numbers of clusters were three (the best) and four. The findings from the two clustering algorithms were similar to those of other studies, classifying *5/*5 as a lowest activity group and genotypes containing duplicated alleles (i.e., CYP2D6*1/*2N) as a highest activity group. The validation of the k-means clustering results with data from the 71 subjects revealed relatively high concordance rates: 92.8% and 73.9% in three and four clusters, respectively. Additionally, color visualization allowed for rapid interpretation of results. Although the clustering approach to predict CYP2D6 phenotype from CYP2D6 genotype is not fully complete, it provides general information about the genotype to phenotype relationship, including rare genotypes with only one subject.

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Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians

Cited by 79 publications

References 0 publications

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

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

Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms

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