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  • 1
    Keywords: 3-aminobenzanthrone, 3-nitrobenzanthrone, ACTIVATION, ADDUCTS, animals, Benz(a)Anthracenes, biotrans
    Abstract: 3-aminobenzanthrone (3-ABA) is the metabolite of the carcinogenic air pollutant 3-nitrobenzanthrone (3-NBA). 3-ABA was investigated for its ability to induce cytochrome P450 1A1 (CYP1A1) and NAD(P)H:quinone oxidoreductase (NQO1) in kidney and lung of rats, and for the influence of such induction on DNA adduct formation by 3-ABA and 3-NBA. NQO1 is the enzyme that reduces 3-NBA to N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) and CYP1A enzymes oxidize 3-ABA to the same intermediate. When activated by cytosolic and and/or microsomal fractions isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney, both compounds generated the same DNA-adduct pattern, consisting of five adducts. When pulmonary cytosols isolated from rats that had been treated i.p. with 40 mg/kg bw of 3-ABA were incubated with 3-NBA, DNA adduct formation was up to 1.7-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. In contrast, no induction of NQO1 expression by 3-ABA treatment was found in the kidney. Incubations of 3-ABA with renal and pulmonary microsomes of 3-ABA-treated rats led to an increase of up to a 4.5-fold in DNA-adduct formation relative to controls. The stimulation of DNA-adduct formation correlated with a higher protein expression and activity of CYP1A1 induced by 3-ABA. These results show that by inducing lung and kidney CYP1A1 and NQO1, 3-ABA increases its own enzymatic activation as well as that of the environmental pollutant, 3-NBA, thereby enhancing the genotoxic and carcinogenic potential of both compounds
    Type of Publication: Journal article published
    PubMed ID: 19398038
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  • 2
    Keywords: brain ; CANCER ; IRRADIATION ; radiotherapy ; tumor ; Germany ; PROSTATE ; THERAPY ; TOXICITY ; COHORT ; RISK ; GENE ; GENES ; TISSUE ; TUMORS ; validation ; radiation ; PATIENT ; MARKER ; RISK-FACTORS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; MUTATION ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; cancer risk ; RISK FACTOR ; HEAD ; NETHERLANDS ; NORMAL TISSUE ; NECK-CANCER ; brain tumor ; BRAIN-TUMORS ; head and neck cancer ; THERAPIES ; brain tumors ; RISK-FACTOR ; CANCERS ; CANCER-RISK ; GENOME-WIDE ASSOCIATION ; Genetic ; Genome-wide association studies ; cellular response ; CELLULAR-RESPONSE ; BRAIN-TUMOR
    Abstract: Radiotherapy is an important weapon in the treatment of cancer, but adverse reactions developing in the co-irradiated normal tissue can be a threat for patients. Early reactions might disturb the usual application schedule and limit the radiation dose. Late appearing and degenerative reactions might reduce or destroy normal tissue function. Genetic markers conferring the ability to identify hyper-sensitive patients in advance would considerably improve therapy. Association studies on genetic variation and occurrence of side effects should help to identify such markers. This survey includes published studies and novel data from our own laboratory. It illustrates the presence of candidate polymorphisms in genes involved in the cellular response to irradiation which could be used as predictive markers for radiosensitivity in breast or prostate cancer patients. For other tumor types such as head and neck cancers or brain tumors, the available data are much more limited. In any case, further validation of these markers is needed in large patient cohorts with systematically recorded data on side effects and patient characteristics. Genetic variation contributing to radiosensitivity should be screened on a broader basis using newly developed, more comprehensive approaches such as genome-wide association studies
    Type of Publication: Journal article published
    PubMed ID: 19022265
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  • 3
    Keywords: RISK ; GENETIC POLYMORPHISMS ; ASSOCIATION ; IDENTIFICATION ; HUMANS ; CHROMOSOMAL-ABERRATIONS ; micronuclei ; HUMAN-LYMPHOCYTES ; HUMAN-POPULATIONS ; OXIDATIVE DNA-DAMAGE ; Benzene ; PERSONAL EXPOSURE ; S-PMA ; URBAN
    Abstract: An integrated approach based on environmental and biological monitoring, including the analysis of biomarkers of exposure [excretion of S-phenylmercapturic acid (S-PMA)], early biological effects [micronucleus (MN) frequency] and susceptibility (genetic polymorphisms), was applied to characterize benzene exposure in a group of 70 traffic policemen and 40 employees of the city of Bologna, Italy. Median personal benzene exposure was 6.55-fold higher for traffic policemen than for controls (P〈0.0001). This higher exposure was confirmed by a significant, 2.53-fold higher S-PMA excretion in traffic policemen compared with that observed for indoor workers (P〈0.0001). Median MN frequency was also significantly higher in policemen compared with indoor workers (P=0.001), emphasizing the genotoxic effect potentially associated with benzene exposure. With regard to biomarkers of susceptibility, the analysis revealed that high epoxide hydrolase (mEH) (predicted) enzyme activity was significantly correlated with a lower median MN frequency (P=0.003). A gene-gender interaction was observed for the glutathione-S-transferase M1 (GSTM1) genotype. The GSTM1-null genotype was associated with a significantly higher median MN frequency in men, not in women. Statistical analysis did not reveal any association between the presence of the protective allele, pushing the pathway towards benzene detoxification, and MN frequency or S-PMA excretion. Even though there are some limitations in the study, our results indicate that policemen are exposed to higher levels of benzene than individuals spending most of the time indoors. This higher exposure may contribute to DNA damage, suggesting an increase health risk from traffic benzene emission. Finally, a more comprehensive study is warranted in order to better elucidate the involvement of EPHX1 genotypes combination in benzene genotoxicity.
    Type of Publication: Journal article published
    PubMed ID: 20951227
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  • 4
    Keywords: CANCER ; RISK ; GENE-EXPRESSION ; CARCINOGENESIS ; BARRIER FUNCTION ; KERATINOCYTE DIFFERENTIATION ; ATOPIC-DERMATITIS ; REPOPULATION ; FILAGGRIN ; SPACE EXPLORATION
    Abstract: Outside the protection of Earth's atmosphere, astronauts are exposed to low doses of high linear energy transfer (LET) radiation. Future NASA plans for deep space missions or a permanent settlement on the moon are limited by the health risks associated with space radiation exposures. There is a paucity of direct epidemiological data for low dose exposures to space radiation-relevant high LET ions. Health risk models are used to estimate the risk for such exposures, though these models are based on high dose experiments. There is increasing evidence, however, that low and high dose exposures result in different signaling events at the molecular level, and may involve different response mechanisms. Further, despite their low abundance, high LET particles have been identified as the major contributor to health risk during manned space flight. The human skin is exposed in every external radiation scenario, making it an ideal epithelial tissue model in which to study radiation induced effects. Here, we exposed an in vitro three dimensional (3-D) human organotypic skin tissue model to low doses of high LET oxygen (O), silicon (Si) and iron (Fe) ions. We measured proliferation and differentiation profiles in the skin tissue and examined the integrity of the skin's barrier function. We discuss the role of secondary particles in changing the proportion of cells receiving a radiation dose, emphasizing the possible impact on radiation-induced health issues in astronauts.
    Type of Publication: Journal article published
    PubMed ID: 25839759
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  • 5
    Keywords: DIESEL EXHAUST ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; GENETIC POLYMORPHISMS ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; reductive activation ; QUINONE OXIDOREDUCTASE ; NAD(P)H-QUINONE OXIDOREDUCTASE ; CYTOCHROMES P450 1A1
    Abstract: 3-Nitrobenzanthrone (3-NBA), a carcinogenic air pollutant, was investigated for its ability to induce cytochrome P450 (CYP) 1A1/2 and NAD(P)H:quinone oxidoreductase (NQO1) in liver, kidney and lung of rats treated by intra-tracheal instillation. The organs used were from a previous study performed to determine the persistence of 3-NBA-derived DNA adducts in target and non-target tissues (Bieler et al., Carcinogenesis 28 (2007) 1117-1121, [22]). NQO1 is the enzyme reducing 3-NBA to N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) and CYP1A enzymes oxidize a human metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), to yield the same reactive intermediate. 3-NBA and 3-ABA are both activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and from liver and kidney. Each compound generated the same five DNA adducts detectable by (32)P-postlabelling. When hepatic cytosols from rats treated with 0.2 or 2 mg/kg body weight of 3-NBA were incubated with 3-NBA, DNA adduct formation was 3.2- and 8.6-fold higher, respectively, than in incubations with cytosols from control animals. Likewise, cytosols isolated from lungs and kidneys of rats exposed to 3-NBA more efficiently activated 3-NBA than those of control rats. This increase corresponded to an increase in protein levels and enzymatic activities of NQO1. Incubations of hepatic, pulmonary or renal microsomes of 3-NBA-treated rats with 3-ABA led to an 9.6-fold increase in DNA-adduct formation relative to controls. The highest induction in DNA-adduct levels was found in lung. The stimulation of DNA-adduct formation correlated with expression of CYP1A1/2 induced by the intra-tracheal instillation of 3-NBA. The results demonstrate that 3-NBA induces NQO1 and CYP1A1/2 in livers, lungs and kidneys of rats after intra-tracheal instillation, thereby enhancing its own genotoxic and carcinogenic potential. (c) 2010 Elsevier B.V. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 21167309
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  • 6
    Abstract: PURPOSE: The XPC gene is involved in DNA damage recognition in the nucleotide excision repair pathway (NER). We investigated the additive effects of single nucleotide polymorphisms (SNPs) in bladder-cancer patients and population controls for three XPC polymorphisms: A499V (C〉T), K939Q (A〉C), and poly AT (PAT, -/+). EXPERIMENTAL DESIGN: 311 bladder-cancer patients from a population-based cohort and 337 population controls were genotyped using the PCR-restriction fragment length polymorphism (RFLP) technique. RESULTS: We found complete linkage between the K939Q (A〉C) and PAT (-/+) polymorphisms and therefore only the K939Q (A〉C) polymorphism was included in analyses. The over all estimated odds ratio was 1.7 (95% CI 1.3-2.4) for A499V (C〉T) and 1.4 (95% CI 1.0-2.0) for K939Q (A〉C). The associated odds ratio increase with the variant allele homozygotes was six-fold for the A499V (C〉T) and three-fold for the K939Q (A〉C) polymorphism (OR=5.7, 95% CI 3.4-9.5 and OR=2.6, 95% CI 1.3-5.6, respectively). The variant allele haplotype of the two polymorphisms (T(499)C(939)) was associated with a nearly four fold increased odds ratio compared to the common allele haplotype (C(499)A(939)) (OR=3.6, 95% CI:1.9-6.9). Combined genotype analysis showed an increased disease association with increasing number of variant alleles (p〈0.0001), with a dominant effect of the A499V polymorphism. In addition we observed association of the disease with increasing number of variant alleles for the A499V polymorphism and an early age at diagnosis (p=0.004). CONCLUSIONS: Our results suggest an association between the XPC genotypes of the A499V, K939Q and PAT polymorphisms and urinary-bladder cancer. We propose a poly-allelic effect of these polymorphisms where the cumulative effect on disease becomes higher than the individual allelic effects.
    Type of Publication: Journal article published
    PubMed ID: 20887739
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  • 7
    Keywords: IN-VITRO ; INHIBITOR ; METABOLISM ; DNA ADDUCT FORMATION ; LIVER-MICROSOMES ; RAT ; SUDAN-I ; AROMATIC-AMINES ; SUSCEPTIBILITY ; HEMOGLOBIN ADDUCTS ; FREE-RADICALS ; o-anisidine ; CYTOCHROMES P450 ; ENVIRONMENTAL-POLLUTANT ; 2-NITROANISOLE CARCINOGENICITY ; N-(2-Methoxyphenyl)hydroxylamine ; o-Nitroanisole
    Abstract: N-(2-Methoxyphenyl)hydroxylamine is a component in the human metabolism of two industrial and environmental pollutants and bladder carcinogens, viz. 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole), and it is responsible for their genotoxicity. Besides its capability to form three deoxyguanosine adducts in DNA, N-(2-methoxyphenyl)-hydroxylamine is also further metabolized by hepatic microsomal enzymes. To investigate its metabolism by human hepatic microsomes and to identify the major microsomal enzymes involved in this process are the aims of this study. N-(2-Methoxyphenyl)hydroxylamine is metabolized by human hepatic microsomes predominantly to o-anisidine, one of the parent carcinogens from which N-(2-methoxyphenyl)hydroxylamine is formed, while o-aminophenol and two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, are minor products. Selective inhibitors of microsomal CYPs, NADPH:CYP reductase and NADH:cytochrome-b(5) reductase were used to characterize human liver microsomal enzymes reducing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. Based on these studies, we attribute the main activity for this metabolic step in human liver to CYP3A4, 2E1 and 2C (more than 90%). The enzymes CYP2D6 and 2A6 also partake in this N-(2-methoxyphenyl)hydroxylamine metabolism in human liver, but only to approximately 6%. Among the human recombinant CYP enzymes tested in this study, human CYP2E1, followed by CYP3A4, 1A2, 2B6 and 2D6, were the most efficient enzymes metabolizing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. The results found in this study indicate that genotoxicity of N-(2-methoxyphenyl)hydroxylamine is dictated by its spontaneous decomposition to nitrenium/carbenium ions generating DNA adducts, and by its susceptibility to metabolism by CYP enzymes.
    Type of Publication: Journal article published
    PubMed ID: 21946300
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