RESUMEN
The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P=0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P=0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmaco-genomics in tailoring tamoxifen treatment.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Neoplasias de la Mama/prevención & control , Citocromo P-450 CYP2D6/genética , Resistencia a Antineoplásicos/genética , Tamoxifeno/uso terapéutico , Arilsulfotransferasa/genética , Estudios de Casos y Controles , Ensayos Clínicos como Asunto , Citocromo P-450 CYP2C19 , Femenino , Humanos , Italia , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
BACKGROUND: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen. PATIENTS AND METHODS: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography-tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR. RESULTS: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype. CONCLUSION: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.
Asunto(s)
Antineoplásicos Hormonales/farmacocinética , Arilsulfotransferasa/genética , Neoplasias de la Mama/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Tamoxifeno/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Arilsulfotransferasa/metabolismo , Biotransformación/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/enzimología , Citocromo P-450 CYP2D6/metabolismo , Femenino , Dosificación de Gen , Frecuencia de los Genes , Genotipo , Humanos , Persona de Mediana Edad , Noruega , Polimorfismo de Longitud del Fragmento de Restricción , Tamoxifeno/análogos & derivados , Tamoxifeno/sangreRESUMEN
We have developed a method for the determination of tamoxifen (tam) and its metabolites 4-hydroxytamoxifen (4OHtam), N-demethyltamoxifen (NDtam), N-dedimethyltamoxifen (NDDtam), tamoxifen-N-oxide (tamNox), and 4-hydroxy-N-demethyltamoxifen (4OHNDtam) in 50 microl human serum. Serum proteins were precipitated with acetonitrile. Deuterated-tamoxifen (D5 tam) was added as internal standard. Sample supernatant was injected into an on-line reversed-phase extraction column coupled with a C18 analytical column and analytes were detected by tandem mass spectrometry. The lower limits of quantification were 0.25 ng/mL for 4OHtam, NDtam and tam, 1.0 ng/mL for NDDtam and tamNox. Ranges of within- and between-day variation were 2.9-15.4% and 4.4-12.9%, respectively.
Asunto(s)
Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Tamoxifeno/sangre , Neoplasias de la Mama/tratamiento farmacológico , Fraccionamiento Químico/métodos , Humanos , Sensibilidad y Especificidad , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismo , Tamoxifeno/uso terapéuticoRESUMEN
Samples of medicinal cod liver oil collected from four of the main producers in Norway have been investigated for content of microorganism. Viable counts for bacteria and fungi were found to be low. No coliform bacteria, coagulase positive Staphylococcus or Pseudomonas could be detected. The findings suggest that the main part of the flora found in cod liver oil belongs to the family Micrococcaceae. Several of the isolated colonies showed lipolytic activity.