title: Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses.
abstract: We tested the influence of four polymorphisms and gene duplication in CYP2D6 on in vivo enzyme activity in a Chilean mestizo population in order to identify the most relevant genetic profiles that account for observed phenotypes in this ethnic group. CYP2D6*2 (2850C>T), *3 (2549A>del), *4 (1846G>A), *17 (1023C>T) and gene duplication were determined by PCR-RFLP or PCRL in a group of 321 healthy volunteers. Individuals with different variant alleles were phenotyped by determining debrisoquine 4-hydroxylase activity as a metabolic ratio (MR) using a validated HPLC assay. Minor allele frequencies were 0.41, 0.01, 0.12 and 0.00 for CYP2D6*2, *3, *4 and *17 variants, respectively, and the duplication frequency was 0.003. Genotype analysis correlated with phenotypes in 18 of 23 subjects (78.3%). 11 subjects were extensive metabolizers (EM), 8 were intermediate metabolizers (IM), 2 were poor metabolizers (PM) and 2 were ultra-rapid metabolizers (UM) which is fairly coincident with expected phenotypes metabolic ratios ranged from 0.11 to 126.41. The influence of CYP2D6*3 was particularly notable, although only heterozygote carriers were present in our population. Individuals homozygous for *4 were always PM. As expected, the only subject with gene duplication was UM. In conclusion, there was a clear effect of genotype on observed CYP2D6 activity. Classification of EM, PM and UM through genotyping was useful to characterize CYP2D6 phenotype in the Chilean mestizo population.
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile; Department of Medical Technology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Nelson
authors.initials: N
authors.lastname: Varela
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile. Electronic address: lquinone@med.uchile.cl.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Quiñones
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Jana
authors.initials: J
authors.lastname: Stojanova
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Joselyn
authors.initials: J
authors.lastname: Garay
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile; Environmental Health Program, School of Public Health, Faculty of Medicine, University of Chile, Chile.
authors.forename: Dante
authors.initials: D
authors.lastname: Cáceres
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cespedes
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Sasso
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Carla
authors.initials: C
authors.lastname: Miranda
mesh_terms: D000293:Adolescent; D000328:Adult; D002677:Chile; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D020440:Gene Duplication; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D007199:Indians, South American / Q000235:genetics; D007700:Kinetics; D008297:Male; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin
keywords: CYP2D6; Debrisoquine; Debrisoquine (PubChem CID: 2966); Debrisoquine 4-hydroxylase; Genotype; Phenotype; Polymorphism