RESUMO
Aim: We evaluated the potential influence of genetic (CYP3A5, EPHX1, NR1I2, HNF4A, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2-rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2-rs3814055 and EPHX1-rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2, EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.
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Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Receptor de Pregnano X/genética , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Carbamazepina/efeitos adversos , Carbamazepina/farmacocinética , Quimioterapia Combinada , Epóxido Hidrolases/genética , Etnicidade , Feminino , Variação Genética , Humanos , Lamotrigina/efeitos adversos , Lamotrigina/uso terapêutico , Masculino , México , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Fenitoína/uso terapêutico , Medicina de Precisão , Centros de Atenção Terciária , Adulto JovemRESUMO
Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p < 0.004) in the activity of CYP1A2 between male and female subjects. The number of CYP2C19 (p < 0.0001) and CYP2D6 (p < 0.0001) active alleles were shown inversely correlated with their corresponding MR, although there were marked genotype-phenotype discrepancies. There was an actual enzyme capacity overlapping (MR) between genotypically Poor (gPMs) and Extensive Metabolizers (gEMs) of 3.14% subjects for CYP2D6 and 0.94% for CYP2C9. Similarly, there was an overlapping for metabolic phenotypes of 11.48% of genotypically ultrarapid metabolizers (gUMs) for CYP2C19 and 2.09% for CYP2D6 and gEMs. Therefore, the current approach for metabolic phenotype prediction based just on genotype does not predict properly for all individuals within this Nicaraguan Mestizo population, thus representing a potential barrier for the clinical implementation of personalized medicine in this region. However, it is necessary to improve the prediction of phenotype from genotype in order to improve the pharmacogenetic implementation in populations with specific ethnic backgrounds.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Adulto , Alelos , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Nicarágua , Farmacogenética/métodos , Fenótipo , Polimorfismo Genético/genética , Medicina de Precisão , Grupos Raciais/genética , Adulto JovemRESUMO
Background: Interethnic differences in CYP2D6 allele frequency have been demonstrated across Latin-American countries. Only one previous study describing CYP2D6 genotypes in Colombian population has been performed. Thus, this study aimed to evaluate the CYP2D6 genetic variability in a mestizo Colombian population, as well as the similarities and differences concerning other Hispanic mestizo (HM) populations. Methodology: Two hundred and twelve unrelated healthy Colombian subjects were studied, in which different CYP2D6 polymorphisms were analyzed by extra long-PCR and real-time PCR. Results & discussion: A high percentage of ultrarapid metabolizers (18.4%) was found, representing the highest frequency calculated within the HM populations studied. However, the percentage of poor metabolizers (4.7%) was similar to those previously reported in HM populations.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Citocromo P-450 CYP2D6/genética , Hispânico ou Latino/genética , Alelos , População Negra/genética , Colômbia/epidemiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Fenótipo , Polimorfismo Genético , PrevalênciaRESUMO
Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.
Assuntos
Anticonvulsivantes/sangue , Epilepsia/sangue , Epilepsia/genética , Indígenas Norte-Americanos/genética , Lamotrigina/sangue , Variantes Farmacogenômicos/genética , Adolescente , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Humanos , Lamotrigina/administração & dosagem , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
A long-standing question and dilemma in precision medicine is whether and to what extent genotyping or phenotyping drug metabolizing enzymes such as CYP2D6 can be used in real-life global clinical and societal settings. Although in an ideal world using both genotype and phenotype biomarkers are desirable, this is not always feasible for economic and practical reasons. Moreover, an additional barrier for clinical implementation of precision medicine is the lack of correlation between genotype and phenotype, considering that most of the current methods include only genotyping. Thus, the present study evaluated, using dextromethorphan as a phenotyping probe, the relationship between CYP2D6 phenotype and CYP2D6 genotype, especially for the ultrarapid metabolizer (UM) phenotype. We report in this study, to the best of our knowledge, the first comparative clinical pharmacogenomics study in a Cuban population sample (N = 174 healthy volunteers) and show that the CYP2D6 genotype is not a robust predictor of the CYP2D6 ultrarapid metabolizer (mUM) status in Cubans. Importantly, the ultrarapid CYP2D6 phenotype can result in a host of health outcomes, such as drug resistance associated with subtherapeutic drug concentrations, overexposure to active drug metabolites, and altered sensitivity to certain human diseases by virtue of altered metabolism of endogenous substrates of CYP2D6. Hence, phenotyping tests for CYP2D6 UMs appear to be a particular necessity for precision medicine in the Cuban population. Finally, in consideration of ethical and inclusive representation in global science, we recommend further precision medicine biomarker research and funding in support of neglected or understudied populations worldwide.
Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Medicina de Precisão/métodos , Adulto , Cuba , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Farmacogenética/métodos , FenótipoRESUMO
AIM: To determine allele and genotype frequencies of genes influencing anti-epileptic drug therapy in Mexican-Mestizo (MM) healthy volunteers, and to evaluate whether these are different from those reported for other populations. SUBJECTS & METHODS: Thirty-nine variants of CYP3A5, EPHX1, NR1I2, HNF4A, UGT1A1, UGT2B7, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1 were genotyped in 300 MM healthy volunteers. RESULTS: All studied alleles were presented in MM, except for seven UGT1A1 variants (*6-8, 14, 15, 27 and 29). Allele and genotype frequencies showed interethnic variations when compared with European, Asian and African populations. Allele frequencies of greater than 30% were observed in ten genes. CONCLUSION: The results presented regarding the frequencies and interethnic differences of these polymorphisms should be taken into account for future pharmacogenetic studies of anti-epileptic drugs in MM patients with epilepsy.
RESUMO
AIM: To analyze the distribution of CYP2D6 variants in two ethnically-related Mexican Native and Mestizo populations cohabitating the same econiche and their relationships with a distant Mestizo community. MATERIALS & METHODS: 314 volunteers were genotyped for CYP2D6 gene variants (*2, *3, *4, *6, *10, *13, *17, *35 and *41) using predesigned TaqMan probes. CYP2D6*5 and CYP2D6 wtxN were assessed by XL-PCR. RESULTS: CYP2D6*1, *2, *4 and *10 variants represented above 80.9% of total alleles. Chiapanecan communities showed low allele diversity compared with the northeastern population. Principal component analyses demonstrated clustering of both Mestizo populations. Variants associated to ultrarapid and poor metabolism were rare in Natives. CONCLUSION: Sharing of CYP2D6 alleles in both Chiapanecan populations suggests an ongoing gene-flow. Original submitted 8 December 2014; Revision submitted 13 February 2015.
Assuntos
Citocromo P-450 CYP2D6/genética , Etnicidade/etnologia , Etnicidade/genética , Variação Genética/genética , Indígenas Norte-Americanos/etnologia , Indígenas Norte-Americanos/genética , Ecossistema , Frequência do Gene/genética , Humanos , México/etnologia , Vigilância da População/métodosRESUMO
AIM: In previous CYP2D6 genotyping studies in Mexican-Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. MATERIALS & METHODS: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican-Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. RESULTS: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. CONCLUSION: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican-Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations.
Assuntos
Citocromo P-450 CYP2D6/genética , Variações do Número de Cópias de DNA/genética , Indígenas Norte-Americanos/genética , Adulto , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , MéxicoRESUMO
UDP-glucuronosyltransferase 1A4 (UGT1A4) is a phase II drug-metabolizing enzyme that catalyzes the glucuronidation of many clinically-important drugs. Interethnic differences in the genetic polymorphism of UGT1A4 have been reported; however, there is no information in Mexican Mestizos (MMs) and Spaniards (SPs). Furthermore, MM is an admixed population with 26 % of Caucasian genes mainly from Spain. Therefore, this study aimed to investigate the potential differences between 318 SPs and 248 MMs healthy individuals regarding UGT1A4*1b, UGT1A4*2 and UGT1A4*3 alleles and to compare the observed frequencies with those previously reported in different populations. The allelic frequencies of the three UGT1A4 polymorphisms showed interethnic differences between MMs and SPs (p < 0.05). The analyzed SNPs variants in this genetic region were not in linkage disequilibrium (LD) for the MM population, suggesting that these mutations have arisen independently in the same genetic background. In contrast, UGT1A4*2 and UGT1A4*3 were in LD in the SP population. Comparison of present data with other in different ethnic groups revealed that the frequencies of UGT1A4*2 and UGT1A4*3 in SP were similar to other Caucasians and higher than in Asians, whereas in MMs were lower than in Caucasians and higher than in Asians only for UGT1A4*2. Present results could be helpful to improve the use of UGT1A4 drug substrates in order to adjust them to the ethnic background of a given population, specifically for Hispanics.
Assuntos
Estudos de Associação Genética , Glucuronosiltransferase/genética , Desintoxicação Metabólica Fase II/genética , Adulto , Idoso , Povo Asiático , Feminino , Frequência do Gene , Hispânico ou Latino/genética , Humanos , Desequilíbrio de Ligação , Masculino , Americanos Mexicanos/genética , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espanha , População Branca/genéticaRESUMO
Meeting report of the "Second Symposium on Pharmacology of Cytochrome P450 and Transporters" organized by the Cuban Society of Pharmacology in collaboration with the European Society of Pharmacogenetics and Theranostics (ESPT) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (www.ribef.com). The Symposium covered different topics on pharmacogenetics and its clinical implications, focusing on Latin-American populations. The activities of the ESPT were also presented and discussed. The topics addressed were regulatory aspects, the use of pharmacogenetics in pre-clinical research, herbal medicine, and natural products, ending with a discussion about translation into clinical practice, specifically for cardiovascular disorders and psychiatry. Finally, the implication for population diversity in Latin America was also discussed. The RIBEF initiative represents a promising step towards the inclusion of Latin American populations among those to benefit from the implementation of pharmacogenetics in clinical practice. Among current RIBEF activities, the CEIBA.FP Consortium aims to study the variability of pheno- and genotypes in Hispanics that are relevant to pharmacogenetics. For this purpose, populations from Mexico, Cuba, Nicaragua, Costa Rica, Ecuador, Colombia, Brasil, Perú, Chile, Uruguay, Argentina, Portugal, and Spain are currently being studied. The meeting's main conclusion was that population pharmacogenetic studies as well as academic clinical trials might need to be conducted in the different geographic locations/countries. This is important in order to improve drug safety, dosage recommendations, and pharmacovigilance programs, because environmental and ethnic factors vary across locations.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Medicina Herbária , Transtornos Mentais/tratamento farmacológico , Farmacogenética , Doenças Cardiovasculares/genética , Humanos , América Latina , Transtornos Mentais/genéticaRESUMO
PURPOSE: Cytochrome P450 2D6 (CYP2D6) genotypes and the dextromethorphan/dextrorphan (DXM/DXT) metabolic ratio (MR), which is a marker of CYP2D6 activity, were studied in 118 unrelated healthy Ecuadorians. METHODS: Genotyping of CYP2D6 was performed by amplification of entire CYP2D6 gene by XL-PCR for CYP2D6*5 and multiplication alleles and by real time-PCR for CYP2D6 *2, *3, *4, *6, *10, *17, *29, *35, *41, and copy number. The plasma levels of DXM and its metabolite DXT were determined on a high-performance liquid chromatography-UV system. RESULTS: The proportions of non-functional alleles were 0.4, 10.6, 0.8, 2.1, and 0% for CYP2D6*3, *4, *4 × N, *5, and *6, respectively. Genotypically, only one of the subjects (0.9%) was homozygous for two inactive alleles and phenotypically classified as a poor metabolizer (PM). The MRs (mean ± standard deviation) corresponding to "activity scores" of 0, 0.5, 1, 1.5, 2, and 2.5 were 10.57 (n = 1), 1.63 ± 0.35 (n = 2), 1.16 ± 0.74 (n = 29), 1.00 ± 0.47 (n = 8), 1.24 ± 0.82 (n = 76), and 1.30 ± 0.32 (n = 2), respectively. CONCLUSIONS: Our data suggest that only 1% of subjects of this Ecuadorian population were PMs and that none were phenotypically ultrarapid metabolizers, which is in agreement with previous findings in other Amerindian populations.
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Antitussígenos/farmacocinética , Citocromo P-450 CYP2D6/genética , Dextrometorfano/farmacocinética , Polimorfismo Genético , Adolescente , Adulto , Alelos , Antitussígenos/sangue , Biotransformação , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/sangue , Dextrorfano/sangue , Equador , Feminino , Dosagem de Genes , Frequência do Gene , Estudos de Associação Genética , Humanos , Hidroxilação , Masculino , Adulto JovemRESUMO
Patients treated with antiepileptic drugs can exhibit large interindividual variability in clinical efficacy or adverse effects. This could be partially due to genetic variants in genes coding for proteins that function as drug metabolizing enzymes, drug transporters or drug targets. The purpose of this article is to provide an overview of the current knowledge on the pharmacogenetics of two commonly prescribed antiepileptic drugs with similar mechanisms of action; phenytoin (PHT) and lamotrigine (LTG). These two drugs have been selected in order to model the pharmacogenetics of Phase I and Phase II metabolism for PHT and LTG, respectively. In light of the present evidence, patients treated with PHT could benefit from CYP2C9 and CYP2C19 genotyping/phenotyping. For those under treatment with LTG, UGT1A4 and UGT2B7 genotyping might be of clinical use and could contribute to the interindividual variability in LTG concentration to dose ratio in epileptic patients.
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Anticonvulsivantes/metabolismo , Fenitoína/metabolismo , Triazinas/metabolismo , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Epilepsia/tratamento farmacológico , Genótipo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Lamotrigina , Farmacogenética , Fenitoína/efeitos adversos , Fenitoína/uso terapêutico , Polimorfismo de Nucleotídeo Único , Triazinas/efeitos adversos , Triazinas/uso terapêuticoRESUMO
The aim of this study was to explain the variability of CYP2D6 activity by the identification of CYP2D6 deletion and multiplications, and the single-nucleotide polymorphisms (SNPs) -1584C-->G, 31G-->A and 2988G-->A in Mexican Mestizo and Tepehuano subjects. One hundred twelve Mestizos and 99 Tepehuano Amerindians were studied, who were previously phenotyped with dextromethorphan. The frequencies of CYP2D6*2A [-1584C-->G] and *35 [-1584C-->G, 31G-->A] were 10.7 and 4.1%, respectively, in Mestizos, which is evidently a trend towards an extensive metabolism in carriers of the -1584G change. In Tepehuanos, *2A was identified with a frequency of 20%, and the allele *35 was not found. The frequencies of CYP2D6*5 (deletion) and *41[2988G-->A] were 1.3 and 2.2% in Mestizos and 0.5 and 1% in Tepehuanos, respectively. The SNP 2988A was found to be significantly related with the intermediate metabolizer phenotype in Mestizos (R = 0.309; n = 88; p = 0.006). The multiplications had frequencies of 4.1% in Mestizos and 1.5% in Tepehuanos. Only in the Mestizos did the presence of multiplications significantly decrease the DM/DX (dextromethorphan/dextrorphan) values (R = 0.273; n = 88; p = 0.016). The polymorphisms studied had different frequencies between Tepehuanos and Mestizos (p < 0.001); however, in the Tepehuano group these had a low influence on their phenotypic expression. It helps to understand the genotype-phenotype relationships of CYP2D6 in our studied populations.
Assuntos
Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/metabolismo , Indígenas Norte-Americanos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Citocromo P-450 CYP2D6/genética , Feminino , Deleção de Genes , Duplicação Gênica , Frequência do Gene , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , FenótipoRESUMO
OBJECTIVES: Our group has previously show that interindividual variability in CYP2D6 hydroxylation capacity was related to personality differences in cognitive social anxiety. Thus, we aimed to analyze whether this relationship between personality and CYP2D6 phenotype and genotype was found in a similar population of healthy volunteers from a different latitude and culture by using the same methodology. METHODS: A total of 253 university students and staff from Havana Psychiatric Hospital and Calixto García Medical School in Cuba completed the Karolinska Scales of Personality (KSP), and were evaluated on debrisoquine hydroxylation capacity and CYP2D6 genotypes. KSP scores were compared between four groups, divided according to their CYP2D6 metabolic capacity: one of poor and three of extensive metabolizers. Furthermore, KSP scores were compared between another four different groups divided according to their number of CYP2D6 active genes: zero, one, two, and more than two. RESULTS: In Cubans, the differences in cognitive social anxiety-related personality traits across the four CYP2D6 hydroxylation capacity groups were strikingly similar to those found in Spaniards. These differences also came out to be significant for psychic anxiety (p = 0.02) and socialization (p = 0.02). The same pattern of results obtained for the subscales of psychic anxiety, socialization, psychasthenia and inhibition of aggression with regard to phenotype in both the Cuban and Spanish studies were seen with regard to CYP2D6 genotypes. CONCLUSIONS: Corroborating these results further strengthens evidence of the relationship between CYP2D6 metabolic capacity and personality. In this population of healthy Cuban volunteers, the CYP2D6 hydroxylation capacity was related to the degree of anxiety and socialization. These results support the postulated reduction of serotonin in CYP2D6 poor metabolizers, which may be associated with a cluster of behavioral traits (e.g., anxiety, impulsivity). Thus, research is warranted to determine CYP2D6 functional implications for interindividual differences in vulnerability to neuropsychiatric diseases and drug response.
Assuntos
Citocromo P-450 CYP2D6/genética , Personalidade/genética , Polimorfismo Genético , Adolescente , Adulto , Ansiedade/genética , Cuba , Citocromo P-450 CYP2D6/metabolismo , Debrisoquina/farmacocinética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Determinação da Personalidade , Fenótipo , EspanhaRESUMO
BACKGROUND AND OBJECTIVE: CYP2D6 metabolic capacity shows genetic polymorphism. Two metabolic phenotypes, poor and extensive, can be determined by the ratio of debrisoquine to its metabolite in urine (MR). A subgroup of ultrarapids has been also described. We analyzed the inter-ethnic differences on the polymorphic hydroxylation of debrisoquine in a Cuban population in comparison to Spaniards. PATIENTS AND METHOD: MR in a Cuban population of 260 white and mestizo healthy volunteers was studied and compared to 925 Spanish healthy volunteers. RESULTS: The frequency of poor metabolizer in Cubans (4.6%) was almost identical to that found in Spaniards (4.9%). However, ultrarapids were lower in Cubans (3.8%) than in Spaniards (5.2%). MR in Cuban-mestizo extensive metabolizers was higher than in white (p<0.05). CONCLUSIONS: Interethnic differences on debrisoquine hydroxylation have been demonstrated in a Cuban population. Furthermore, differences on the frequency of ultrarapids between Cubans and Spaniards have been shown. These results could explain inter-individual and interethnic differences on drug response such as side effects or therapeutic failures among Cuban patients receiving treatment with CYP2D6 substrates.