A high frequency (7–10%) of CYP2D6 ultrarapid metabolizers estimated from the genotype (gUMs) has been claimed to exist among Spaniards and Southern Europeans. However, methodological aspects such as the inclusion of individuals carrying non-active multiplied alleles as gUMs may have led to an overestimation. Thus, this study aimed to analyze the gUM frequency (considering only those carrying more than two active genes) in 805 Spanish healthy volunteers studied for CYP2D6*2, *3, *4, *5, *6, *10, *17, *35, *41, and multiplications. Second, all worldwide studies reporting gUM frequencies were reviewed in order to evaluate potential misclassifications. The gUM frequency in this Spanish population was 5.34%, but increased to 8.3% if all individuals with CYP2D6 multiplications were classified as gUMs without considering the activity of the multiplied alleles. Moreover, among all reviewed worldwide studies only 55.6% precisely determined whether the multiplied alleles were active. Present results suggest that the evaluation of CYP2D6 ultrarapid metabolism should be standarized, and that the frequency of gUMs should be reconsidered in Spaniards and globally.
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Ingelman-Sundberg M . Genetic polymorphisms of cytochrome. P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005; 5: 6–13.
Kawanishi C, Lundgren S, Agren H, Bertilsson L . Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol 2004; 59: 803–807.
Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther 2004; 75: 386–393.
Peñas-Lledo EM, Trejo HD, Dorado P, Ortega A, Jung H, Alonso E et al. CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients. Mol Psychiatry 2013; 18: 8–9.
Prescribing Information about Codeine, 2013 Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022402s006lbl.pdf.
Codeine-containing medicinal products for the treatment of cough or cold in paediatric patients, 2015 Available at http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Codeine_cough_or_cold_in_children/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500186522.pdf.
Zackrisson AL, Lindblom B, Ahlner J . High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther 2010; 88: 354–359.
Peñas-Lledó EM, Dorado P, Aguera Z, Gratacós M, Estivill X, Fernández-Aranda F et al. High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders. Mol Psychiatry 2011; 16: 691–692.
Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, Vaquero-Lorenzo C, Baca-García E, LLerena A . CYP2D6 and the severity of suicide attempts. Pharmacogenomics J 2012; 13: 179–184.
Peñas-Lledó E, Guillaume S, Naranjo MEG, Delgado A, Jaussent I, Blasco-Fontecilla H et al. A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances. Pharmacogenomics J 2015; 15: 172–176.
LLerena A, Dorado P, Peñas-Lledó EM . Pharmacogenetics of debrisoquine and its use as a marker of CYP2D6 hydroxylation capacity. Pharmacogenomics J 2009; 10: 17–28.
LLerena A, Naranjo MEG, Rodrigues-Soares F, Peñas-Lledó EM, Fariñas H, Tarazona-Santos E . Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metab Toxicol 2014; 10: 1569–1583.
LLerena A, Berecz R, De la Rubia A, Norberto MJ, Benítez J . Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity. Ther Drug Monit 2000; 22: 397–401.
Berecz R, LLerena A, De La Rubia A, Gomez J, Kellermann M, Dorado M . Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients. Pharmacopsychiatry 2002; 35: 231–234.
Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS . The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 2008; 83: 234–242.
Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M . Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441–446.
Agúndez JAG, Ledesma MC, Ladero JM, Benítez J . Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharm Ther 1995; 57: 265–269.
Bernal ML, Sinues B, Johansson I, McLellan RA, Wennerholm A, Dahl ML et al. Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics 1999; 9: 657–660.
Scordo MG, Caputi AP, D’Arrigo C, Fava G, Spina E . Allele and genotype frequencies of CYP2C9 CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 2004; 50: 195–200.
Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Xanthi A, Tavridou A et al. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol 2007; 21: 419–426.
Correia C, Santos P, Coutinho AM, Vicente AM . Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample. Cell Biochem Funct 2009; 27: 251–255.
Albuquerque J, Ribeiro C, Naranjo MEG, LLerena A, Grazina M CEIBA.FP Consortium of the Ibero–American Network of Pharmacogenetics & Pharmacogenomics RIBEF. Characterization of CYP2D6 genotypes and metabolic profiles in the Portuguese population: pharmacogenetic implications. Personal Med 2013; 10: 709–718.
Dorado P, Heras N, Machín E, Hernández F, Terán E, LLerena A . CYP2D6 genotype and dextromethorphan hydroxylation phenotype in an Ecuadorian population. Eur J Clin Pharmacol 2012; 68: 637–644.
Dorado P, Cáceres MC, Pozo-Guisado E, Wong ML, Licinio J, LLerena A . Development of a PCR-based strategy for CYP2D6 genotyping including gene multiplication of worldwide potential use. Biotechniques 2005; 39: 571–574.
LLerena A, Dorado P, Ramírez R, González I, Álvarez M, Peñas-Lledó EM et al. CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans. Pharmacogenomics J 2012; 12: 176–183.
Lazalde-Ramos BP, Martínez-Fierro Mde L, Galaviz-Hernández C, Garza-Veloz I, Naranjo MEG, Sosa-Macías M et al. CYP2D6 gene polymorphisms and predicted phenotypes in eight indigenous groups from Northwestern Mexico. Pharmacogenomics J 2014; 15: 339–348.
Céspedes-Garro C, Naranjo MEG, Ramírez R, Serrano V, Fariñas H, Barrantes R et al. Pharmacogenetics in Central American healthy volunteers: interethnic variability. Drug Metabol Personal Ther 2015; 30: 19–31.
Scott SA, Edelmann L, Kornreich R, Erazo M, Desnick RJ . CYP2C9, CYP2C19 and CYP2D6 allele frequencies in the Ashkenazi Jewish population. Pharmacogenomics J 2007; 8: 721–730.
Moya G, Dorado P, Ferreiro V, Naranjo MEG, Peñas-Lledó EM, LLerena A. High frequency of CYP2D6 ultrarapid metaboliser genotypes ultrarapids in an Ashkenazi Jewish population from Argentina. Pharmacogenomics J 2016; Mdoi: 10.1038/tpj.2016.27 [e-pub ahead of print].
Dodgen TM, Hochfeld WE, Fickl H, Asfaha SM, Durandt C, Rheeder P et al. Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study. BMC Med Genet 2013; 14: 20.
Dodgen TM, Labuschagne CJ, van Schalkwyk A, Steffens FE, Gaedigk A, Cromarty AD et al. Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort. Pharmacogenomics J 2015 doi:10.1038/tpj.2015.76, [e-pub ahead of print].
Riffel AK, Dehghani M, Hartshorne T, Floyd KC, Leeder JS, Rosenblatt KP et al. CYP2D7 sequence variation interferes with TaqMan CYP2D6 (*) 15 and (*) 35 genotyping. Front Pharmacol 2016; 6: 312.
López M, Guerrero J, Jung-Cook H, Alonso ME . CYP2D6 genotype and phenotype determination in a Mexican Mestizo population. Eur J Clin Pharmacol 2005; 61: 749–754.
Beer B, Erb R, Pitterl F, Niederstätter H, Maroñas O, Gesteira A et al. CYP2D6 genotyping by liquid chromatography-electrospray ionization mass spectrometry. Anal Bioanal Chem 2011; 400: 2361–2370.
Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Mörike K et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 1998; 8: 15–26.
Rideg O, Háber A, Botz L, Szücs F, Várnai R, Miseta A et al. Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population. Cell Biochem Funct 2011; 29: 562–568.
Griese EU, Asante-Poku S, Ofori-Adjei D, Mikus G, Eichelbaum M . Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics 1999; 9: 715–723.
Zihlif M, Imraish A, Irshaid YM . Frequency of certain single-nucleotide polymorphisms and duplication of CYP2D6 in the Jordanian population. Genet Test Mol Biomarkers 2012; 16: 1201–1205.
McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M . Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 1997; 7: 187–191.
Wan YJ, Poland RE, Han G, Konishi T, Zheng YP, Berman N et al. Analysis of the CYP2D6 gene polymorphism and enzyme activity in African-Americans in Southern California. Pharmacogenetics 2001; 11: 489–499.
Fohner A, Muzquiz LI, Austin MA, Gaedigk A, Gordon A, Thornton T et al. Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes. Pharmacogenet Genomics 2013; 23: 403–414.
Varela N, Quiñones LA, Stojanova J, Garay J, Cáceres D, Cespedes S et al. Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses. Pharmacol Res 2015; 101: 124–129.
Isaza CA, Henao J, López AM, Cacabelos R . Isolation, sequence and genotyping of the drug metabolizer CYP2D6 gene in the Colombian population. Methods Find Exp Clin Pharmacol 2000; 22: 695–705.
Casner PR . The effect of CYP2D6 polymorphisms on dextromethorphan metabolism in Mexican Americans. J Clin Pharmacol 2005; 45: 1230–1235.
Mendoza R, Wan YJ, Poland RE, Smith M, Zheng Y, Berman N et al. CYP2D6 polymorphism in a Mexican American population. Clin Pharmacol Ther 2001; 70: 552–560.
Bozina N, Granić P, Lalić Z, Tramisak I, Lovrić M, Stavljenić-Rukavina A . Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003; 44: 425–428.
Buzková H, Pechandová K, Slanar O, Perlík F . Frequency of single nucleotide polymorphisms of CYP2D6 in the Czech population. Cell Biochem Funct 2008; 26: 76–81.
Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW . Sequence-based CYP2D6 genotyping in the Korean population. Ther Drug Monit 2006; 28: 382–387.
Cai WM, Nikoloff DM, Pan RM, de Leon J, Fanti P, Fairchild M et al. CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing. Pharmacogenomics J 2006; 6: 343–350.
Rodríguez-Santiago B, Brunet A, Sobrino B, Serra-Juhé C, Flores R, Armengol L et al. Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Mol Psychiatry 2010; 15: 1023–1033.
Martis S, Mei H, Vijzelaar R, Edelmann L, Desnick RJ, Scott SA . Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation. Pharmacogenomics J 2013; 13: 558–566.
Tremmel R, Klein K, Winter S, Schaeffeler E, Zanger UM . Gene copy number variation analysis reveals dosage-insensitive expression of CYP2E1. Pharmacogenomics J 2015 doi:10.1038/tpj.2015.69, [e-pub ahead of print].
Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 2015; 98: 127–134.
Griese EU, Ilett KF, Kitteringham NR, Eichelbaum M, Powell H, Spargo RM et al. Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in aborigines from Western Australia. Pharmacogenetics 2001; 11: 69–76.
Garcia-Barceló M, Chow LY, Lam KL, Chiu HF, Wing YK, Waye MM . Occurrence of CYP2D6 gene duplication in Hong Kong Chinese. Clin Chem 2000; 46: 1411–1413.
Lee SJ, Lee SS, Jung HJ, Kim HS, Park SJ, Yeo CW et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 2009; 37: 1464–1470.
Luo HR, Aloumanis V, Lin KM, Gurwitz D, Wan YJ . Polymorphisms of CYP2C19 and CYP2D6 in Israeli ethnic groups. Am J Pharmacogenomics 2004; 4: 395–401.
Aynacioglu AS, Sachse C, Bozkurt A, Kortunay S, Nacak M, Schröder T et al. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 1999; 66: 185–192.
Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmöller J, Frötschl R, Köpke K et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003; 59: 303–312.
Rebsamen MC, Desmeules J, Daali Y, Chiappe A, Diemand A, Rey C et al. The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J 2009; 9: 34–41.
Kohlrausch FB, Gama CS, Lobato MI, Belmonte-de-Abreu P, Gesteira A, Barros F et al. Molecular diversity at the CYP2D6 locus in healthy and schizophrenic Southern Brazilians. Pharmacogenomics J 2009; 10: 1457–1466.
Chou WH, Yan FX, Robbins-Weilert DK, Ryder TB, Liu WW, Perbost C et al. Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships. Clin Chem 2003; 49: 542–551.
Montané-Jaime LK, Lalla A, Steimer W, Gaedigk A . Characterization of the CYP2D6 gene locus and metabolic activity in Indo- and Afro-Trinidadians: discovery of novel allelic variants. Pharmacogenomics J 2013; 14: 261–276.
Céspedes-Garro C, Jiménez-Arce G, Naranjo MEG, Barrantes R, LLerena A CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics & Pharmacogenomics RIBEF. Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans. Rev Biol Trop 2014; 62: 1659–1671.
Sosa-Macías M, Dorado P, Alanis-Bañuelos RE, LLerena A, Lares-Asseff I . Influence of CYP2D6 deletion, multiplication, -1584C—>G, 31G—>A and 2988G—>A gene polymorphisms on dextromethorphan metabolism among Mexican Tepehuanos and Mestizos. Pharmacology 2010; 86: 30–36.
López-López M, Peñas-Lledó E, Dorado P, Ortega A, Corona T, Ochoa A et al. CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas. Pharmacogenomics J 2014; 15: 1859–1865.
Perez-Paramo YX, Hernandez-Cabrera F, Dorado P, LLerena A, Muñoz-Jimenez S, Ortiz-Lopez R et al. Interethnic relationships of CYP2D6 variants in native and Mestizo populations sharing the same ecosystem. Pharmacogenomics J 2015; 16: 703–712.
Luo HR, Gaedigk A, Aloumanis V, Wan YJ . Identification of CYP2D6 impaired functional alleles in Mexican Americans. Eur J Clin Pharmacol 2005; 61: 797–802.
Gaedigk A, Bradford LD, Marcucci KA, Leeder JS . Unique CYP2D6 activity distribution and genotype-phenotype discordance in Black Americans. Clin Pharmacol Ther 2002; 72: 76–89.
Wennerholm A, Johansson I, Massele AY, Lande M, Alm C, Aden-Abdi Y et al. Decreased capacity for debrisoquine metabolism among Black Tanzanians: analyses of the CYP2D6 genotype and phenotype. Pharmacogenetics 1999; 9: 707–714.
This study was supported by Junta de Extremadura, AEXCID 13IA001 (to SIFF), Instituto de Salud Carlos III-Sara Borrell program (CD13/00348, FdA), Union Europea-Fondo Social Europeo (FSE) and Junta de Extremadura Consejería de Economía e Infraestructuras (TE14002, ADR), and coordinated by the network Red Iberoamericana de Farmacogenética y Farmacogenómica (www.ribef.com).
The authors declare no conflict of interest.
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Naranjo, M., de Andrés, F., Delgado, A. et al. High frequency of CYP2D6 ultrarapid metabolizers in Spain: controversy about their misclassification in worldwide population studies. Pharmacogenomics J 16, 485–490 (2016). https://doi.org/10.1038/tpj.2016.47