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Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were(More)
Chemical chaperones are low molecular weight compounds known to stabilize proteins in vitro. Recently it was shown that, in transfected cells, these molecules can also correct the defective folding of some mutant proteins. Hyperphenylalaninemia (HPA) has been proposed to be classified as a "conformational disease," since it has been shown that the majority(More)
In order to elucidate the molecular basis of phenylketonuria (PKU) in Portugal, a detailed study of the Portuguese mutant phenylalanine hydroxylase (PAH) genes was performed. A total of 222 mutant alleles from 111 PKU families were analysed for 26 mutations and restriction fragment length polymorphismlvariable number tandem repeat (RFLP/VNTR) haplotypes. It(More)
Modulation of CYP3A1 and CYP3A2 mRNA expression by dexamethasone and by phenobarbital has been studied in immature (21-day-old) and adult (90-day-old) rat liver. Positive modulation of these forms by both agents markedly declines with the age of the animals. However, CYP3A2 mRNA, although physiologically extinguished in the adult females, still responds to(More)
Induction of CYP3A genes by the ligand-activated pregnane-X-receptor (PXR) involves the interaction of other as yet unidentified liver transcription factors. Here we show that the CYP3A1 promoter contains two active sites controlled by the CCAAT/enhancer-binding protein alpha (C/EBPalpha), previously shown to regulate a number of liver stress response(More)
A clone was isolated from a cDNA library constructed from phenobarbital-treated Wistar rat liver and proven to correspond to the full-length mRNA of a polymorphic variant of Sprague-Dawley CYP3A1. Eight nucleotide differences were detected in a single 76-nucleotide stretch and confirmed to be present in the genomic clone. They are seated in a region(More)
Brain defective cholesterol homeostasis has been associated with neurologic diseases, such as Alzheimer's and Huntington's disease. The elimination of cholesterol from the brain involves its conversion into 24(S)-hydroxycholesterol by CYP46A1, and the efflux of this oxysterol across the blood-brain barrier. Herein, we identified the regulatory elements and(More)
Poly(ADP-ribose)polymerase (PARP) has been implicated in DNA repair mechanisms and the associated activity shown to markedly increase after DNA damage in carcinogen-treated cells. A defective DNA repair has been associated to the aetiology of human cancers. In order to assess the potential role of this enzyme in cellular response to DNA damage by(More)
Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by(More)
MPTP-induced dopaminergic neurotoxicity involves major biochemical processes such as oxidative stress and impaired energy metabolism, leading to a significant reduction in the number of nigrostriatal dopaminergic neurons. Glutathione S-transferase pi (GSTpi) is a phase II detoxifying enzyme that provides protection of cells from injury by toxic chemicals(More)