RESUMO
CYP2D6 is one of the most polymorphic of the cytochrome P450 enzymes. Genetic differences in this enzyme have been reported in whites, blacks, and Asians. However, there is very little information about polymorphisms of this enzyme in Mexican Americans. The objectives of the present study were to assess the metabolic activity of CYP2D6 in a Mexican American population using dextromethorphan and to correlate this metabolic activity with a genotypic analysis. The sample consisted of 50 Mexican American subjects and 25 non-Mexican American controls. Overnight urine samples were collected and analyzed by high-performance liquid chromatography to calculate the metabolic ratio of dextromethorphan to dextrorphan. Blood samples were collected for genotypic analysis of CYP2D6 alleles. The frequency of the poor metabolizer phenotype was the same in the Mexican American group and the non-Mexican American group (6% vs 5.5%). The frequency of alleles in the Mexican American group was similar to frequencies published in other reports for non-Hispanic whites: *4 = 0.17, *5 = 0.02, *10 = 0.01, *17 = 0.02, *xN = 0.03. These results indicate that compared with non-Hispanic whites, Mexican Americans have a similar proportion of poor metabolizer phenotype and similar genetic polymorphisms of CYP2D6.
Assuntos
Citocromo P-450 CYP2D6/genética , Dextrometorfano/farmacocinética , Americanos Mexicanos/genética , Polimorfismo Genético , Adulto , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/urina , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Fenótipo , TexasRESUMO
OBJECTIVE: Although CYP2D6 genetic polymorphism plays an important role in interindividual and interethnic variability in drug response, very few pharmacogenetic data are available from Hispanic populations, including Mexicans. For this purpose, this study was undertaken to determine CYP2D6 genotype and phenotype in a healthy Mexican Mestizo population. METHODS: Genotyping of five CYP2D6 mutant alleles by PCR-RFLP, and CYP2D6*5 and duplicated CYP2D6 alleles by long-PCR was performed in two hundred and forty three Mexican Mestizos. Of these, one hundred subjects were also phenotyped using dextromethorphan as the probe drug. RESULTS: The frequency of CYP2D6*2, *3, *4, *5, *10, *17 was 19.34%, 1.44%, 11.21%, 2.67%, 12.45%, and 1.65%, respectively, while duplicated CYP2D6 alleles were found in 12.76% of the 243 genotyped subjects. Among the 100 phenotyped subjects, we identified ten (10%, 95% confidence interval of 4.12-15.9) individuals as poor metabolizers by using the published antimode for Caucasians. The mean log10 dextromethorphan/dextrorphan ratio of the total sample was -2.05. The mean (SD) of the log10 MR in the CYP2D6 subgroups was UM = -2.6 (0.86); EM = -2.09 (0.98); IM = -1.71 (1.06); and PM = 0.42 (0.625). These data show a trend toward a smaller mean log MR (higher enzyme activity) as the number of active alleles increases. CONCLUSIONS: The PM frequency of CYP2D6 in the population studied was 10%, which is very similar to Spanish Caucasians. The observed frequency of the CYP2D6 alleles tested was unique for the Mexican Mestizo sample analyzed, and in accordance to the Caucasian, Asian and African admixture in this population.
Assuntos
Citocromo P-450 CYP2D6/genética , Frequência do Gene , Adulto , Alelos , Cromatografia Líquida de Alta Pressão , DNA/genética , Dextrometorfano/farmacocinética , Dextrometorfano/urina , Feminino , Genética Populacional , Genótipo , Humanos , Masculino , México/etnologia , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoAssuntos
Citocromo P-450 CYP2D6/genética , Dextrometorfano/metabolismo , Polimorfismo Genético , Adulto , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/urina , Dextrorfano/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , UruguaiRESUMO
The polymorphic oxidative metabolism of debrisoquine and sparteine were discovered in the seventies by Mahgoub and Eichelbaum. Since then, many other therapeutic substances were added and one of these drugs is dextromethorphan. The object of this investigation was to ascertain the distribution of the oxidative phenotype of dextromethorphan in the Uruguayan population. The drug and its metabolite, dextrorphan, were quantified in the urine of 165 healthy volunteers by a modificacion of an HPLC method by Chen et al. The metabolic ratio was calculated and frequency distribution histograms were drawn. By inspection of the histogram two antimodes can be assigned which determine three sub-populations: on one side the fast extensive metabolizers (n = 30, 18.2 per cent), in the middle the extensive metabolizers (n = 123, 74.5 per cent) and on the other extreme of the histogram the slow metabolizers (n = 12, 7.3 per cent). No other studies have confirmed thus far this trimodal distribution. This research will be continued by genotyping the populations studied in order to confirm these findings and to elucidate the underlying genetic mechanisms of the polymorphism.
Assuntos
Humanos , Masculino , Feminino , Adulto , Dextrometorfano/urina , Dextrorfano/urina , Enzimas/genética , Oxirredutases O-Desmetilantes/metabolismo , Polimorfismo Genético , Fenótipo , UruguaiRESUMO
The polymorphic oxidative metabolism of debrisoquine and sparteine were discovered in the seventies by Mahgoub and Eichelbaum. Since then, many other therapeutic substances were added and one of these drugs is dextromethorphan. The object of this investigation was to ascertain the distribution of the oxidative phenotype of dextromethorphan in the Uruguayan population. The drug and its metabolite, dextrorphan, were quantified in the urine of 165 healthy volunteers by a modificacion of an HPLC method by Chen et al. The metabolic ratio was calculated and frequency distribution histograms were drawn. By inspection of the histogram two antimodes can be assigned which determine three sub-populations: on one side the fast extensive metabolizers (n = 30, 18.2 per cent), in the middle the extensive metabolizers (n = 123, 74.5 per cent) and on the other extreme of the histogram the slow metabolizers (n = 12, 7.3 per cent). No other studies have confirmed thus far this trimodal distribution. This research will be continued by genotyping the populations studied in order to confirm these findings and to elucidate the underlying genetic mechanisms of the polymorphism. (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Polimorfismo Genético , Enzimas/genética , Oxirredutases O-Desmetilantes/metabolismo , Dextrometorfano/urina , Dextrorfano/urina , Fenótipo , UruguaiRESUMO
Es de interés para el farmacólogo clínico general el estudio de los factores genéticos que determinan la respuesta a los medicamentos. El polimorfismo genético de la debrisoquina/sparteína ha sido descrito en la década del 70 y ha tomado gran relevancia dado que un número significativo de fármacos utilizados en terapéutica clínica se oxidan por la misma vía metabólica que éstos. El dextrometorfan es un antitusígeno que cosegrega con la debrisoquina y su uso es más seguro. En el presente estudio se caracterizó la distribución de la O-demetilación del dextrometorfan en la población uruguaya (fenotipificación) mediante el cociente metabólico (CM). El objetivo del estudio fue conocer el comportamiento farmacogenético de nuestra población para esta vía metabólica. Se fenotipificaron 165 voluntarios en condiciones basales y se encontró un 6,3 por ciento de metabolizadores lentos. El histograma de frecuencia del CM muestra algunas peculiaridades que se discuten en el texto
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Dextrometorfano/metabolismo , Polimorfismo Genético , Dextrometorfano/urina , Fenótipo , UruguaiRESUMO
Es de interés para el farmacólogo clínico general el estudio de los factores genéticos que determinan la respuesta a los medicamentos. El polimorfismo genético de la debrisoquina/sparteína ha sido descrito en la década del 70 y ha tomado gran relevancia dado que un número significativo de fármacos utilizados en terapéutica clínica se oxidan por la misma vía metabólica que éstos. El dextrometorfan es un antitusígeno que cosegrega con la debrisoquina y su uso es más seguro. En el presente estudio se caracterizó la distribución de la O-demetilación del dextrometorfan en la población uruguaya (fenotipificación) mediante el cociente metabólico (CM). El objetivo del estudio fue conocer el comportamiento farmacogenético de nuestra población para esta vía metabólica. Se fenotipificaron 165 voluntarios en condiciones basales y se encontró un 6,3 por ciento de metabolizadores lentos. El histograma de frecuencia del CM muestra algunas peculiaridades que se discuten en el texto (AU)