Genetic polymorphism of drug-metabolizing enzymes and styrene-induced DNA damage.
ABSTRACT A cross-sectional study was carried out on 48 workers exposed to styrene and 14 unexposed healthy controls in order to investigate the genotoxic potential of styrene exposure. DNA damage was assessed in peripheral blood leukocytes (WBCs) by the comet assay. Polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and the gene encoding microsomal epoxide hydrolase (EPHX) were characterized to assess their possible modifying role in styrene metabolism and subsequent DNA damage. Exposed workers showed significantly higher levels of DNA damage compared to controls. Among workers, the GSTM1 and GSTT1 polymorphisms significantly affected comet parameters. Subjects bearing a GSTM1pos genotype showed a significantly higher proportion of damaged nuclei compared to people lacking GSTM1-1 expression (GSTM1null), whereas GSTT1pos workers showed significantly lower DNA damage than GSTT1null individuals. Styrene-7,8-oxide (SO)-induced DNA damage was assessed in vitro in WBCs isolated from the healthy controls. A clear dose-response relationship at micromolar doses of SO was found for the whole group. WBCs collected from subjects bearing the homozygous wildtype GSTP1 genotype showed a significant protection compared to cells from subjects bearing at least one GSTP1 variant allele. The field survey confirms that styrene exposure is associated with increased DNA damage and indicates a modulating role for GSTM1 and GSTT1 genotypes. In vitro experiments suggest that the extent of SO-induced DNA strand breaks depends, at least in part, on interindividual differences in GSH-conjugation capabilities.
- SourceAvailable from: Antonio Mutti
Article: Nuovi indicatori di effetto[Show abstract] [Hide abstract]
ABSTRACT: NEW EFFECT BIOMARKERS. The major research goals for researchers developing biomarkers of effect are the development and validation of biomarkers that permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This article reviews the most recent analytical methodologies, validation studies and field trials together with auditing and quality assessment of the necessary data based on scientific grounds. Consideration is given to new developments in the relatively young field of toxicogenomics, possibly leading to the identification of early changes that may lead to both cancer and non-cancer end points. Although the creation and development of reliable databases integrating information from genomic and proteomic research programmes should offer a contribution to the prediction of risks and prevention of diseases related to chemical exposure, the most promising future application of these technologies lies in the molecular diagnosis of diseases whose nosography will probably be redefined.
- Cancer Letters - CANCER LETT. 01/2010; 12(4):181-182.
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ABSTRACT: Ab-initio molecular orbital calculations were carried out for a series of phosphazine compounds, (NPX2)n, X=H, F, Cl, and Br, n=2 through 6, in order to study the electronic structure of such compounds and explore their use as model compounds for the bulk polymer. Calculations were carried out at the Hartree–Fock level of theory, using all-electron triple-zeta plus polarization basis sets for all atoms. Full geometry optimizations followed by frequency calculations were performed. Although most species adopted hightly symmetric geometries they were often significantly nonplanar. Optimized geometries are general agreement with geometry's inferred from solution phase IR studies. The geometries of the eight membered and larger rings are very dependent on the identity of X. Ionization energies for this series were calculated using electron propagator theory. Good agreement with experimentally observed values is found. Phosphorus d basis functions appear to be serving as polarization functions rather than being formally involved in bonding.Polyhedron 01/2003; 22(3):473-482. · 2.05 Impact Factor