Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

Bernard, Stephen A.; Neville, Kathleen; Nguyen, Anne; Flockhart, David A.

doi:10.1634/theoncologist.11-2-126

Cited by 251 publications

(188 citation statements)

References 64 publications

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“…Pertinent to the current discussion of tamoxifen metabolism, the CYP2D6*4 allele [130] is estimated to have a frequency of 12-23% in Causasians, 1.2-7% in black Africans and 0-2.8% in Asians [127,128]. A lower estimate of (<10%) of the PM phenotype is presented by Bernard and coworkers [131].…”

Section: Tamoxifen Metabolism Todaymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Tamoxifen Metabolism Todaymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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“…The 291 allele *10 was detected with a prevalence of 16,5%, which is higher than the expected 292 based on large European population studies and according to CYP2D6 Allelic Variation 293 Summary Table in http://www.cypalleles.ki.se/cyp2d6.htm [30,31] but is in accordance 294 with a recent study for Portuguese population [32]. CYP2D6*10 isn't a null allele but it 295 can decrease the enzymatic activity and change the substrate specificity of the enzyme 296 [13,[33][34][35].…”

mentioning

confidence: 67%

Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol

Fonseca

Amorim

Costa

et al. 2016

Forensic Science International

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Tramadol concentrations and analgesic effect are dependent on the CYP2D6 enzymatic activity. It is well known that some genetic polymorphisms are responsible for the variability in the expression of this enzyme and in the individual drug response. The detection of allelic variants described as non-functional can be useful to explain some circumstances of death in the study of post-mortem cases with tramadol. A Sanger sequencing methodology was developed for the detection of genetic variants that cause absent or reduced CYP2D6 activity, such as *3, *4, *6, *8, *10 and *12 alleles. This methodology, as well as the GC/MS method for the detection and quantification of tramadol and its main metabolites in blood samples was fully validated in accordance with international guidelines. Both methodologies were successfully applied to 100 post-mortem blood samples and the relation between toxicological and genetic results evaluated. Tramadol metabolism, expressed as its metabolites concentration ratio (N-desmethyltramadol/Odesmethyltramadol), has been shown to be correlated with the poormetabolizer phenotype based on genetic characterization. It was also demonstrated the importance of enzyme inhibitors identification in toxicological analysis. According to our knowledge, this is the first study where a CYP2D6 sequencing methodology is validated and applied to post-mortem samples, in Portugal. The developed methodology allows the data collection of post-mortem cases, which is of primordial importance to enhance the application of these genetic tools to forensic toxicology and pathology. We further state that this paper reports original work and is not under consideration for publication elsewhere. National Institute of Legal Medicine and Forensic SciencesCorresponding author: Suzana Fonseca Contacts:Email: sfonseca@dlinml.mj.pt

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“…The selection of variants should be partially based on the patient population which the laboratory serves; studies have revealed that specific SNPs within germline drug metabolizing genes can be prominent within specific ethnic groups [129]. For example, CYP3A5 is expressed only in approximately 10% of the European population [130].…”

Section: Criteria For Selecting a Genotyping Methodsmentioning

confidence: 99%

Application and Utility of Pharmacogenetics in the Clinical Laboratory

2014

J Analyt Molecul Tech

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The administration of pharmaceuticals presents a challenge for the healthcare system, as inappropriate drug or dose selection can result in diminished therapeutic efficacy or adverse drug reactions. Genetic variability is a major regulator of drug action and should be taken into account during drug and dose selection. The correlation of drug responses (phenotypes) to specific polymorphisms (genotype) has contributed to the development of many targeted genotyping approaches. Incorporation of such testing into the clinical laboratory requires the evaluation of current testing platform characteristics as well as the selection of appropriate polymorphisms to be tested. Here we describe known genotype -phenotype relationships pertinent to drug action and present currently available targeted genotyping platforms for pharmacogenetics (PGx) testing. We additionally discuss considerations regarding platform and polymorphism selection for successful integration of PGx testing into the clinical laboratory and attainment of clinically useful results.

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Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

Cited by 251 publications

References 64 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol

Application and Utility of Pharmacogenetics in the Clinical Laboratory

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