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CYP2D6 Genotype and Debrisoquine Hydroxylation Phenotype in Cubans and Nicaraguans

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CYP2D6 Genotype and Debrisoquine Hydroxylation Phenotype in Cubans and Nicaraguans The Pharmacogenomics Journal (2012) 12, 176–183 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans A LLerena1, P Dorado1, CYP2D6 genotype and debrisoquine metabolic ratio (MR) were analyzed 2 ´ 3,5 in 133 Nicaraguan Mestizos (NMs) and 260 Cubans divided into Cuban R Ramı´rez , I Gonzalez , Mestizos (CMs) and White Cubans (WCs). The frequencies of poor 4 1 MA´lvarez , EM Pen˜as-LLedo´ , metabolizers (MRX12.6) were 6% in NMs, 3.9% in CMs and 5.3% in BPe´rez4 and LR Calzadilla3 WCs. The frequencies of ultrarapid metabolizers (MRp0.1) were 0% in NMs, 2.3% in CMs and 5.3% in WCs. Mean (±s.d.) MR among extensive 1CICAB-CAIBER Centro de Investigacio´n Clı´nica, metabolizers (MRo12.6) was higher in NMs (1.5±1.6; n ¼ 118) than in Hospital Universitario Servicio Extremen˜ode CMs (1.0±1.3; n ¼ 124; P 0.001) and WCs (0.7±1.0; n ¼ 124; P 0.001). Salud SES, Facultad de Medicina Universidad o o de Extremadura, Badajoz, Spain; 2Facultad MR correlated with the ‘activity score’ of CYP2D6 genotypes (Po0.05; de Medicina, UNAM Universidad Auto´noma r ¼À0.55). Mean MR was higher among NMs than WCs and CMs for groups Nacional de Nicaragua, Leo´n, Nicaragua; classified as 1 (P 0.05) or 2 (P 0.01) ‘activity score’. In addition, mean 3 o o Hospital Psiquia´trico de La Habana, La Habana, (±s.d.) MR was higher among subjects carrying CYP2D6*17 than in CYP2D6 Cuba and 4Facultad de Medicina Calixto Garcı´a, Instituto Superior de Ciencias Me´dicas de La wt/wt (Po0.001). The CYP2D6*10 allele was higher in NMs (3.1%) than in Habana, La Habana, Cuba CMs (0.8%; Po0.05) and WCs (0.4%; Po0.05). CYP2D6*17 allele was higher in CMs (10.2%) than WC (2.7%; Po0.005) and NMs (0%). Thus, the Correspondence: variability in CYP2D6 phenotypes found may be related to differences in Dr A Llerena, CICAB Clinical Research Center-Fundesalud, Hospital Universitario allele frequency among groups (that is, CYP2D6*10 and *17 highest in NMs Infanta Cristina, Badajoz 06080, Spain. and CMs, respectively). However, the influence of environmental factors or E-mail: [email protected] alleles different than those studied here cannot be ruled out. The Pharmacogenomics Journal (2012) 12, 176–183; doi:10.1038/tpj.2010.85; published online 7 December 2010 Keywords: CYP2D6; debrisoquine hydroxylation; phenotype; Latinos; Cubans; Nicaraguans Introduction Interethnic differences in cytochrome P450 polymorphism might be partially responsible for the variations in drug disposition between populations. Cytochrome P450 2D6 (CYP2D6) is of great importance for the metabolism of B25% of all clinically used drugs. Phenotyping with specific probe drugs, such as debrisoquine, sparteine or dextromethorphan, allows classifying individuals into two hydroxylation phenotypes: Poor (PMs) and extensive metabolizers (EMs), including a group of individuals with very rapid enzyme activity or the so called ultrarapid metabolizers (UMs).1 The worldwide distribution of PMs varies markedly. In Europe, PMs are more common (5–10%) than in Asia (B1%), whereas in Africa PMs are reported to range from 0 to 19%.2–4 In Latino 5 Current address: Hospital de Llerena, Servicio populations, the frequency of PMs is also variable ranging from 3.2 to 10% Extremen˜o de Salud SES, Spain. (Table 1). In Amerindian groups, PMs range from 0% in Mexican Tepehuano and in Panama´ Cuna to 4.4% in Ngawbes living in Colombia and Panama (Table 1). Received 27 June 2010; revised 27 August 2010; accepted 30 September 2010; However, few studies have estimated the frequency of UMs in Latino or published online 7 December 2010 Amerindian populations, being the frequency in Spaniards of 5.2%.17 CYP2D6 among Cubans and Nicaraguans A LLerena et al 177 Table 1 Percentages of CYP2D6 variant alleles and poor metabolizers in Latino, Amerindian and Spanish populations Populations N Defective alleles Reduced activity alleles Duplicationa % PMsb References 3a 4a 5a 6a 10a 17a Brazilian–African 87 1.2 6.3 4.2 0 4.2 9.2 2.3+1.2 Kohlrausch et al.5 Brazilian–European 92 0 10.3 1.1 2.2 2.7 2.2 4.9+1.6 Kohlrausch et al.5 Colombian 121 1.2 19.4 0.8 0 1.6 1.2 Isaza et al.6 Cuna (Panama) 170 0 (spt) Arias et al.7 89 0 (dbq) Jorge et al.8 Embera (Panama, 153 0 14 0 1.1 6.9 Jorge et al.8 Colombia) 153 2.2 (spt) Jorge et al.8 Mapuche (Chile) 84 0 3.6 4.2 1.8 Mun˜oz et al.9 Mexican–American 349 o1 10.3 2.3 7.4 o1 1 Mendoza et al.10 285 3.2 (dxt) Mendoza et al.10 Mexican–American 264 0.2 10 1.7 0.4 2.8 0.2 0.8 Luo et al.11 236 10 (dxt) Luo et al.11 Mexican–American 50 17 2 1 2 3 Casner12 50 6 (dxt) Casner12 Mexican–Mestizo 243 1.4 11.2 2.7 12.4 1.7 12.8 Lo´pez et al.13 100 10 (dxt) Lo´pez et al.13 Mexican–Mestizo 110 0.9 13.1 0 2.3 Sosa-Macı´as et al.14 88 6.8 (dxt) Sosa-Macı´as et al.14 Ngawbe (Panama, 344 0 17.1 0 0.5 17.5 Jorge et al.8 Colombia) 344 4.4 (spt) Jorge et al.8 Spanish 925 5.2 (dbq) Llerena et al.15 Spanish 327 0.5 18.5 1.4 3.1 2.0 0 4.1+0.3 —c Tepehuano (Mexico) 85 0 0.6 0 0 Sosa-Macı´as et al.14 58 0 (dxt) Sosa-Macı´as et al.14 Uruguayan 302 7.3 (dxt) Estevez et al.16 Abbreviations: dbq; debrisoquine; dxt, dextromethorphan; N, number of subjects; PMs, poor metabolizers; spt sparteine. aDuplications of functional plus non-functional CYP2D6 alleles. bCYP2D6 phenotyping test drugs: dbq, dxt and spt. cLLerena and Dorado, unpublished 2010. The CYP2D6 is a highly polymorphic gene localized phenotype has been only observed in individuals with zero on chromosome 22q13.1. The CYP2D6 alleles are related active genes, whereas using the most common classification to absent, decreased, normal and increased catalytic activ- of 0, 1, 2 and 42 active genes. This correlation has been ity (http://www.cypalleles.ki.se/cyp2d6.htm). CYP2D6*3, largely improved since Gaedigk et al.22 proposed the ‘activity CYP2D6*4, CYP2D6*5, CYP2D6*6 are the most important score’ concept, which has been probed using dextromethor- variants related to absent enzyme activity and CYP2D6*10 phan as substrate test. Therefore, it first appears of scientific and CYP2D6*17 to reduced enzyme activity. The frequency interest to analyze it using debrisoquine, which is one of the of CYP2D6 alleles varies amongst ethnic groups. The most most accurate markers of CYP2D6 hydroxylation capacity. frequent non-functional alleles for Caucasians are in order Second, considering that United States Food and Drug CYP2D6*4, CYP2D6*5 and CYP2D6*3 (Table 1). CYP2D6*10 Association has already approved drugs with prescribing is more frequent in Asians,18 and CYP2D6*17 in Black guidelines targeted toward specific ethnic groups, it is also of Africans.19 Considering that Latinos have besides Caucasian, relevance to study groups that might be representative of Amerindian and African ancestors, a large representation of Latin American populations, including the largest minority non-functional but also of reduced function alleles is (15%) in United States of America. The studied populations expected to be found. The frequency of individuals with in this study resemble the constitution of Latinos; three duplicated CYP2D6 active alleles has been set around 5% in groups with an expected higher Caucasian (White Cubans; Spain,20 0.69% in Asia21 and 29% in Ethiopia.3 However, WC), African (Cuban Mestizos; CM) or Amerindian (Nicar- there are few reports in Latino populations, and it is not aguan Mestizos; NM) ancestry component. Therefore, this clearly shown whether the multiplication is of active alleles study was aimed to determine whether there were differ- (Table 1). ences in the frequency of CYP2D6 PMs and UMs, and the CYP2D6 genotyping is widely used to evaluate enzyme most common and relevant CYP2D6 alleles across the activity, but a perfect match between genotype and studied populations. The genotype–phenotype relationship The Pharmacogenomics Journal CYP2D6 among Cubans and Nicaraguans A LLerena et al 178 using ‘activity score’ was also analyzed, as well as the drug and that of 4-hydroxydebrisoquine in the 0–8 h urine functional implication of the analyzed alleles (for example, output. The antimode for each histogram was calculated CYP2D6*17). according to the Probit plot. Individuals with an MR 412.6 (log10 MRX1.1) were considered as PMs, whereas the rest Materials and methods were classified as EMs. Among EMs, a cut-off point of MRp0.1 was used to classify the UMs.17,15,29 Subjects and procedure The Cuban population was divided into two groups: Genotyping procedure ‘Whites’ WCs that were those individuals with four Blood samples (10 ml) were collected in EDTA tubes, and Caucasian grandparents and ‘Mestizos’ CMs that repre- DNA was extracted using the QIAamp DNA blood kit sented the rest. Debrisoquine hydroxylation phenotype (QIAGEN, Hilden, Germany). The CYP2D6 genotype was was evaluated in 131 WCs, 129 CMs and 133 NMs. The analyzed by PCR and PCR–restriction fragment length CYP2D6 genotype was analyzed in 130 WCs, 126 CMs and polymorphism for the CYP2D6 *3,*4,*5,*6,*10,*17, and 30 98 NMs healthy volunteers.
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