RESUMO
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.
Assuntos
Antineoplásicos Hormonais/farmacocinética , Arilsulfotransferase/genética , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Tamoxifeno/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Arilsulfotransferase/metabolismo , Biotransformação/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/enzimologia , Citocromo P-450 CYP2D6/metabolismo , Feminino , Dosagem de Genes , Frequência do Gene , Genótipo , Humanos , Pessoa de Meia-Idade , Noruega , Polimorfismo de Fragmento de Restrição , Tamoxifeno/análogos & derivados , Tamoxifeno/sangueRESUMO
Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.
Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Ácido Graxo Sintases/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Haloperidol/farmacologia , Hidroximetilglutaril-CoA Sintase/genética , Linhagem Celular Tumoral , Colesterol/biossíntese , Colesterol/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/biossíntese , Ácidos Graxos/genética , Perfilação da Expressão Gênica , Glioma , Humanos , Hidroximetilglutaril-CoA Sintase/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Fatores de Tempo , Regulação para CimaRESUMO
The coffee berry borer beetle Hypothenemus hampei (Ferrari) (Curculionidae: Scolytinae) is the major insect pest of coffee and has spread to most of the coffee-growing countries of the world. This beetle also displays an unusual life cycle, with regular sibling mating. This regular inbreeding and the population bottlenecks occurring on colonization of new regions should lead to low levels of genetic diversity. We were therefore interested in determining the level of nucleotide variation in nuclear and mitochondrial genomes of this beetle worldwide. Here we show that two nuclear loci (Resistance to dieldrin and ITS2) are completely invariant, whereas some variability is maintained at a mitochondrial locus (COI), probably corresponding to a higher mutation rate in the mitochondrial genome. Phylogenetic analysis of the mitochondrial data shows only two clades of beetle haplotypes outside of Kenya, the proposed origin of the species. These data confirm that inbreeding greatly reduces nucleotide variation and suggest the recent global spread of only two inbreeding lines of this bark beetle.
