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1.
Oxidative DNA damage and repair, as measured by 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine and DNA samples were studied in association with work-related diesel exhaust exposure among garage and waste collection workers. Seasonal variations of the urinary 8-OHdG levels in pre- and two post-workshift urine samples of 29 exposed workers and 36 control persons were evaluated. The mean±SE levels of post-workshift 8-OHdG (μmol/mol crea) were 1.52±0.44 in winter and 1.61±0.33 in summer for the exposed workers, and 1.56±0.61 in winter and 1.43±0.49 in summer for the controls, respectively. No significant difference in the urinary 8-OHdG levels between exposed workers and control subjects in winter (p=0.923) and summer (p=0.350) was observed. A linear mixed model, adjusted for years of employment, age, ex/non-smoking and BMI, indicated no significant dose exposure-relationships between the urinary 8-OHdG and 15 PAH air concentrations nor between the 8-OHdG and 7 PAH monohydroxy-metabolites analyzed in the same workers. 8-OHdG was also analyzed in the mononuclear cell DNA of 19 exposed and 18 control subjects. The mean value of 8-OHdG/non-modified 2'-deoxyguanosine (8-OHdG/105 dG±SE) were 4.89±0.17 for the exposed and 4.11±0.16 for the control persons, which showed no correlation with the urinary 8-OHdG levels (r=0.01, n=28, P=0.96). The PAH exposure at workplaces was mainly composed of volatile compounds, particularly naphthalene, suggesting low exposure through the respiratory tract and a low effect of PAH in ROS induction. 相似文献
2.
Bioactivation of cysteine conjugates of 1-nitropyrene oxides by cysteine conjugate beta-lyase purified from Peptostreptococcus magnus.
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To determine the role of cysteine conjugate beta-lyase (beta-lyase) in the metabolism of mutagenic nitropolycyclic aromatic hydrocarbons, we determined the effect of beta-lyase on the mutagenicities and DNA binding of cysteine conjugates of 4,5-epoxy-4,5-dihydro-1-nitropyrene (1-NP 4,5-oxide) and 9,10-epoxy-9,10-dihydro-1-nitropyrene (1-NP 9,10-oxide), which are detoxified metabolites of the mutagenic compound 1-nitropyrene. We purified beta-lyase from Peptostreptococcus magnus GAI0663, since P. magnus is one of the constituents of the intestinal microflora and exhibits high levels of degrading activity with cysteine conjugates of 1-nitropyrene oxides (1-NP oxide-Cys). The activity of purified beta-lyase was optimal at pH 7.5 to 8.0, was completely inhibited by aminooxyacetic acid and hydroxylamine, and was eliminated by heating the enzyme at 55 degrees C for 5 min. The molecular weight of beta-lyase was 150,000, as determined by fast protein liquid chromatography. S-Arylcysteine conjugates were good substrates for this enzyme. As determined by the Salmonella mutagenicity test, 5 ng of beta-lyase protein increased the mutagenicity of the cysteine conjugate of 1-NP 9,10-oxide (10 nmol per plate) 4.5-fold in Salmonella typhimurium TA98 and 4.1-fold in strain TA100. However, beta-lyase had little effect on the cysteine conjugate of 1-NP 4,5-oxide (10 nmol per plate). Both conjugates exhibited only low levels of mutagenicity with nitroreductase-deficient strain TA98NR. In vitro binding of 1-NP oxide-Cys to calf thymus DNA was increased by adding purified beta-lyase or xanthine oxidase.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
3.
The effect of irradiation with wavelengths of 320-418 nm on direct-acting mutagenicity of 1-nitropyrene (1-NP) and particulate-matter extracts of a direct-injecting diesel engine was examined. The activity of samples in the Ames test with and without addition of S9 mix in Salmonella typhimurium strain TA98, TA100 and TA1538 decreased with increasing irradiation energy. Visible light was sufficient to destroy the mutagenicity of a 0.1-mM 1-NP solution. The same was true for particulate matter crude extracts as well as the transitional and oxygenate subfractions isolated by column chromatography. UV spectroscopy, thin-layer chromatography and GC-MS analysis were performed to characterize the irradiation products of 1-NP. The mechanism of photodecomposition of 1-NP at different wavelengths and the significance of this finding for the evaluation of health risks from diesel vehicles are discussed. 相似文献
4.
van Bekkum YM van den Broek PH Scheepers PT Noordhoek J Bos RP 《Chemico-biological interactions》1999,117(1):15-33
1-Nitropyrene (1-NP), a weak carcinogen associated with diesel exhaust particles, has previously been detected in workplace atmospheres with in-use diesel engines and in the general environment. In order to gain insight in its biological fate, a single dose of [14C]-1-NP (27.6 microCi, 750 mg/kg body weight, b.w.) was administered intragastrically to rats and the presence of metabolites in blood and tissue homogenates, and radioactivity associated with blood proteins and tissue DNA, were studied. Early peak levels of radioactivity observed in blood and tissue homogenates indicated a rapid absorption of [14C]-1-NP from the gastrointestinal tract. Metabolite patterns observed in plasma, liver and kidney homogenates strongly suggested an important role of the intestinal microflora in the enterohepatic recirculation, but not in nitroreduction of 1-NP prior to absorption from the gastrointestinal tract. This might explain the low levels of radioactivity associated with blood proteins, since 1-nitrosopyrene, a product of nitroreduction of 1-NP, is likely to be involved in protein binding. Levels of radioactivity associated with plasma proteins were approximately four times higher than the levels of radioactivity associated with hemoglobin (401.0 and 84.1 pmol/g protein per micromol 1-NP kg b.w., respectively, at 24 h). Maximal 25% of the associated radioactivity was released following mild alkaline hydrolysis of either hemoglobin or plasma proteins. 1-Aminopyrene was the only released compound after hydrolysis of hemoglobin. In addition to 1-aminopyrene, two more polar unidentified metabolites were detected following hydrolysis of plasma proteins. Association of radioactivity with DNA was highest in the liver at the first moments of observation (7.4 pmol 14C Eq./mg DNA per micromol 1-NP kg b.w.), but decreased rapidly to levels lower than observed for kidney DNA (max. 3.0 pmol 14C Eq./mg DNA per micromol 1-NP kg b.w. at 24 h). In lungs 8-50 times less radioactivity was associated with DNA than observed in the liver and kidneys. The results of this study show, that 1-NP undergoes an extensive and complex biotransformation in vivo, resulting in a variety of metabolites present in blood and tissue homogenates and a diversity of blood protein adducts. Concentrations of plasma metabolites, blood protein adducts and DNA adducts were rather low. In addition, previous studies also showed relatively low concentrations of metabolites present in urine. Therefore, sensitive and selective methods will be needed in order to evaluate the biological fate of 1-NP, associated with diesel exhaust particles, in humans. 相似文献
5.
Nitropyrene, the predominant nitropolycyclic hydrocarbon found in diesel exhaust, is a mutagenic and tumorigenic environmental pollutant that requires metabolic activation via nitroreduction and ring oxidation. In order to determine the role of ring oxidation in the mutagenicity of 1-nitropyrene, its oxidative metabolites, 1-nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide, were synthesized and their mutation spectra were determined in the coding region of hprt gene of CHO cells by a PCR amplification of reverse-transcribed hprt mRNA, followed by a DNA sequence analysis. A comparison of the two metabolites for mutation frequencies showed that 1-nitropyrene 9,10-oxide was 2-times higher than 1-nitropyrene 4,5-oxide. The mutation spectrum for 1-nitropyrene 4,5-oxide was base substitutions (33/49), one base deletions (11/49) and exon deletions (5/49). In the case of 1-nitropyrene 9,10-oxide, base substitutions (27/50), one base deletions (15/50), and exon deletions (8/50) were observed. Base substitutions were distributed randomly throughout the hprt gene. The majority of the base substitutions in mutant from 1-nitropyrene 4,5-oxide treated cells were A-->G transition (15/33) and G-->A transition (8/33). The predominant base substitution, A-->G transition (11/27) and G-->A transition (8/27), were also observed in mutant from 1-nitropyrene 9,10-oxide treated cells. The mutation at the site of adenine and guanine was consistent with the previous results, where the sites of DNA adduct formed by these compounds were predominant at the sites of purines. A comparison of the mutational patterns between 1-nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide showed that there were no significant differences in the overall mutational spectrum. These results indicate that each oxidative metabolite exhibits an equal contribution to the mutagenicity of 1-nitropyrene, and ring oxidation of 1-nitropyrene is an important metabolic pathway to the formation of significant lethal DNA lesions. 相似文献
6.
Dr. Erik Dybing Jon E. Dahl Frederick A. Beland Snorri S. Thorgeirsson 《Cell biology and toxicology》1986,2(3):341-355
The metabolism and activation of 1-nitropyrene (1-NP) to reactive intermediates by lung microsomes and isolated lung cells was studied. Mutagenicity of 1-NP metabolites was assayed in Salmonella typhimurium TA98NR, a strain lacking a major component of nitroreductase activity. In the presence of NADPH, microsomes from rabbit, rat and hamster lung metabolized 1-NP to mutagenic products to a similar degree. Pretreatment with a mixture of polychlorinated biphenyls (PCB) decreased the formation of mutagenic metabolites by rabbit lung microsomes, but did not affect the production of mutagens by rat or hamster lung microsomes. 3H-1-NP was metabolized to covalently bound protein products at a rate of 82 and 10 pmol/mg by rabbit and hamster lung microsomes, respectively, whereas no binding was detected in rat lung microsomes. PCB-pretreatment increased covalent protein binding of 3 H-1-NP in lung microsomes from hamster and rat, but decreased the binding in rabbit lung microsomes. High performance liquid chromatography analysis indicated that 3H-1-NP was readily converted to ring-hydroxylated products by rabbit and hamster lung microsomes; the rate was much lower with rat lung microsomes. 3H-1-NP was activated to metabolites that covalently bound to protein in isolated rabbit lung cells, with the following rates being observed: Clara cells > lung digest > type II cells. In contrast, covalent protein binding in cells isolated from rat lung was very low. 1-NP was not activated to products mutagenic for S. typhimurium TA 98 N R when co-incubated with cells isolated either from rabbit or rat lung.Abbreviations 1-AP
1-aminopyrene
- DMSO
dimethyl sulfoxide
- EGTA
ethylene glycol-bis(ß-aminoethyl ether)
- EM
electron microscopy
- HEPES
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
- HPBS
HEPES-phosphate-buffered-saline
- HPLC
high performance liquid chromatography
- NBT
nitroblue tetrazolium
- 1-NP
1-nitropyrene
- 1-NP-4,5-diol
trans-4,5-dihydro-4,5-dihydroxy-1-nitropyrene
- 1-NP-9,10-diol
trans-9,10-dihydro-9,10-dihydroxy-1-nitropyrene
- 1-NP-4,5-oxide
1-nitropyrene-4,5-oxide
- 1-NP-9,10-oxide
1-nitropyrene-9,10-oxide
- 3-OH-1-NP
3-hydroxy-1-nitropyrene
- 6-/8-OH-1-NP
a mixture of 6- and 8-hydroxy-1-nitropyrene
- PBS
phosphate-buffered saline
- PCB
a mixture of polychlorinated biphenyls (Aroclor 1254)
- TLC
thin layer chromatography 相似文献
7.
There is growing concern that gastrointestinal exposure to particles is associated with increased risk of toxicity to internal organs and carcinogenicity. The mechanism of action is related to particle-induced oxidative stress and oxidation of DNA. Observations from animal models indicate that gastrointestinal exposure to single-walled carbon nanotubes (SWCNT), fullerenes C60, carbon black, titanium dioxide and diesel exhaust particles generates oxidized DNA base lesions in organs such as the bone marrow, liver and lung. Oral exposure to nanosized carbon black has also been associated with increased level of lipid peroxidation derived exocyclic DNA adducts in the liver, suggesting multiple pathways of oxidative stress for particle-generated damage to DNA. At equal dose, diesel exhaust particles (SRM2975) generated larger levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in rat liver than carbon black (Printex 90) did, whereas exposure to fullerenes C60 and SWCNT was the least potent. This ranking of samples was also observed for oxidatively damaged DNA in cultured cells. The extent of translocation from the gut is largely unresolved. However, there is evidence indicating that gastrointestinal exposure to particulate matter is associated with oxidative damage to DNA and this might be associated with increased risk of cancer. 相似文献
8.
DNA excision repair, as measured by unscheduled DNA synthesis (UDS), was examined in different cell types of rabbit lung exposed to nitropolycyclic aromatic hydrocarbons (NO-PAH) in vitro. Dose-related increases in UDS were observed. 1,6-Dinitropyrene (1,6-DNP) and 1,8-dinitropyrene (1,8-DNP) induced UDS more effectively in alveolar type-II cells compared with Clara cells. On the other hand, 1-nitropyrene (1-NP) caused a weak UDS response in Clara cells but no DNA repair in alveolar type-II cells. 相似文献
9.
An examination of the weak mutagenic response of 1-nitropyrene in Chinese hamster ovary cells 总被引:2,自引:0,他引:2
Incubation of suspension cultures of Chinese hamster ovary (CHO) cells with 1-nitropyrene for as long as 2.5 h failed to induce mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus, while incubation with 1-nitrosopyrene, a reduced derivative of 1-nitropyrene, resulted in a strong mutagenic response. Examination of the metabolites produced during these incubations indicated that 1-nitrosopyrene was rapidly reduced to 1-aminopyrene while 1-nitropyrene was not detectably metabolized. Both compounds produced a single major DNA adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene, in the CHO cells and a strong linear relationship was found between mutation induction and the extent of DNA binding. The low level of adducts produced by 1-nitropyrene was consistent with the weak mutagenic response produced by this compound. These results indicate that both 1-nitropyrene and 1-nitrosopyrene are reduced to a reactive electrophile, presumably N-hydroxy-1-aminopyrene, which produces potentially mutagenic DNA damage in CHO cells. Comparison of the relationship between N-(deoxyguanosin-8-yl)-1-aminopyrene formation and mutation induction in CHO cells with the levels of 1-nitropyrene-induced DNA damage associated with positive responses in other assays of genetic toxicity and with the number of mutations associated with the DNA adducts produced by other agents in CHO cells suggests that the CHO/HGPRT assay may be relatively insensitive to 1-nitropyrene-induced DNA damage. The poor capability of CHO cells in reducing 1-nitropyrene and the relative insensitivity of the assay to the DNA damage produced by this compound may contribute to the weak mutagenic response of 1-nitropyrene in CHO cells. 相似文献
10.
Genotoxicity of pyrene oxide and 1-nitropyrene oxides in hepatocyte primary culture/DNA repair test 总被引:1,自引:0,他引:1
H Mori S Sugie A Okumura A Hara T Kinouchi K Kataoka Y Ohnishi 《Mutation research》1991,262(4):233-238
The genotoxicity of a pyrene oxide, 1-nitropyrene (NP) oxides and other related compounds was examined in the hepatocyte primary culture (HPC)/DNA repair test. Pyrene 4,5-oxide and both 1-NP-4,5-oxide and 1-NP-9,10-oxide elicited clearly positive responses of DNA repair. In this assay, 1-NP itself was weakly positive. However, other related chemicals such as pyrene, 1-nitro-3-hydroxypyrene, 1-nitro-6-hydroxypyrene, and 1-nitro-8-hydroxypyrene did not generate positive responses. 相似文献
11.
Oxidative stress-induced DNA damage by particulate air pollution 总被引:14,自引:0,他引:14
Exposure to ambient air particulate matter (PM) is associated with pulmonary and cardiovascular diseases and cancer. The mechanisms of PM-induced health effects are believed to involve inflammation and oxidative stress. The oxidative stress mediated by PM may arise from direct generation of reactive oxygen species from the surface of particles, soluble compounds such as transition metals or organic compounds, altered function of mitochondria or NADPH-oxidase, and activation of inflammatory cells capable of generating ROS and reactive nitrogen species. Resulting oxidative DNA damage may be implicated in cancer risk and may serve as marker for oxidative stress relevant for other ailments caused by particulate air pollution. There is overwhelming evidence from animal experimental models, cell culture experiments, and cell free systems that exposure to diesel exhaust and diesel exhaust particles causes oxidative DNA damage. Similarly, various preparations of ambient air PM induce oxidative DNA damage in in vitro systems, whereas in vivo studies are scarce. Studies with various model/surrogate particle preparations, such as carbon black, suggest that the surface area is the most important determinant of effect for ultrafine particles (diameter less than 100 nm), whereas chemical composition may be more important for larger particles. The knowledge concerning mechanisms of action of PM has prompted the use of markers of oxidative stress and DNA damage for human biomonitoring in relation to ambient air. By means of personal monitoring and biomarkers a few studies have attempted to characterize individual exposure, explore mechanisms and identify significant sources to size fractions of ambient air PM with respect to relevant biological effects. In these studies guanine oxidation in DNA has been correlated with exposure to PM(2.5) and ultrafine particles outdoor and indoor. Oxidative stress-induced DNA damage appears to an important mechanism of action of urban particulate air pollution. Related biomarkers and personal monitoring may be useful tools for risk characterization. 相似文献
12.
Hilario P Yan S Hingerty BE Broyde S Basu AK 《The Journal of biological chemistry》2002,277(47):45068-45074
In the Ames Salmonella typhimurium reversion assay 1,6- and 1,8-dinitropyrenes (1,6- and 1,8-DNPs) are much more potent mutagens than 1-nitropyrene (1-NP). Genetic experiments established that certain differences in the metabolism of the DNPs, which in turn result in increased DNA adduction, play a role. It remained unclear, however, if the DNP adducts, N-(guanin-8-yl)-1-amino-6 ()-nitropyrene (Gua-C8-1,6-ANP and Gua-C8-1,8-ANP), which contain a nitro group on the pyrene ring covalently linked to the guanine C8, are more mutagenic than the major 1-NP adduct, N-(guanin-8-yl)-1-aminopyrene (Gua-C8-AP). In order to address this, we have compared the mutation frequency of the three guanine C8 adducts, Gua-C8-AP, Gua-C8-1,6-ANP, and Gua-C8-1,8-ANP in a CGCG*CG sequence. Single-stranded M13mp7L2 vectors containing these adducts and a control were constructed and replicated in Escherichia coli. A remarkable difference in the induced CpG deletion frequency between these adducts was noted. In repair-competent cells the 1-NP adduct induced 1.7% CpG deletions without SOS, whereas the 1,6- and 1,8-DNP adducts induced 6.8 and 10.0% two-base deletions, respectively. With SOS, CpG deletions increased up to 1.9, 11.1, and 15.1% by 1-NP, 1,6-, and 1,8-DNP adducts, respectively. This result unequivocally established that DNP adducts are more mutagenic than the 1-NP adduct in the repetitive CpG sequence. In each case the mutation frequency was significantly increased in a mutS strain, which is impaired in methyl-directed mismatch repair, and a dnaQ strain, which carries a defect in proofreading activity of the DNA polymerase III. Modeling studies showed that the nitro group on the pyrene ring at the 8-position can provide additional stabilization to the two-nucleotide extrahelical loop in the promutagenic slipped frameshift intermediate through its added hydrogen-bonding capability. This could account for the increase in CpG deletions in the M13 vector with the nitro-containing adducts compared with the Gua-C8-AP adduct itself. 相似文献
13.
Effects of exposure to diesel exhaust particles (DEP) on pulmonary metabolic activation of mutagenic agents 总被引:1,自引:0,他引:1
Exposure of rats to diesel exhaust particles (DEP) or carbon black (CB) has been shown to induce time-dependent changes in CYP1A1and CYP2B1 in the lung. The present study evaluated the role of these metabolic enzymes on the pulmonary bioactivation of mutagens. Male Sprague-Dawley rats were intratracheally instilled with saline (control), DEP or CB (35 mg/kg body weight) and sacrificed at 1, 3, or 7 days post-exposure. Both control and exposed lung S9 increased the mutagenic activity of 2-aminoanthracene (2-AA), 2-aminofluorene (2-AF), 1-nitropyrene (1-NP), and the organic extract of DEP (DEPE) in Ames tests with Salmonella typhimurium YG1024 in a dose-dependent manner. Lung microsomes prepared form control or particle-exposed S9, but not cytosolic protein, activated 2-AA mutagenicity. Compared to saline controls, CB-exposed S9 was a less potent inducer of 2-AA mutagenicity at all time points, whereas DEP-exposed S9 was less potent than control saline at 3 and 7 days but not 1 day post-exposure. At 3 days post-exposure, DEP- or CB-exposed lung S9 did not significantly affect the mutagenicity of DEPE or 1-NP, when compared to the controls. The mutgenicity of 2-AA, 2-AF, 1-NP, and DEPE were significantly decreased in the presence of inhibitors for CYP1A1 (alpha-naphthoflavone) or CYP2B (metyrapone), but markedly enhanced by CYP1A1 or CYP2B1 supersomes with all the cofactors, suggesting that both CYP1A1 and CYP2B1 were responsible for mutagen activation. These results demonstrated that exposure of rats to DEP or CB altered metabolic activity of lung S9 and S9 metabolic activity dependent mutagen activation. The bioactivation of mutagens are metabolic enzyme- and substrate-specific, and both CYP1A1 and CYP2B1 play important roles in pulmonary mutagen activation. 相似文献
14.
M I Willems W K de Raat J A Wesstra G L Bakker G Dubois W van Dokkum 《Mutation research》1989,222(4):375-391
The occurrence of mutagens in the urine and faeces of a group of car mechanics (n = 8) exposed to high concentrations of diesel exhaust in their working place and of a group of office workers (n = 9) not exposed to diesel exhaust during working hours was compared. The aim of the study was to investigate whether the specific diesel exposure and/or other, more lifestyle-related, factors such as diet had any influence on the mutagenicity of excreta. Faeces were collected and pooled for a consecutive period of 48 h, urine was collected in the same period, but in 4 separate portions representing the urine produced during the day and at night on the 2 collection days. Information about food intake was collected by a 2-day dietary record method. Smoking habits and medicinal drug use were recorded as well. Air particulates were collected in and outside the garage during working hours. The mutagenicity of extracts of air particulates (methanol extracts), urine (XAD-2 and XAD-7 extracts) and faeces (acetone, ether and ether-NaOH extracts) was examined in the Ames test. The results did not suggest that exposure to diesel exhaust mutagens enhanced the incidence and/or degree of either faecal or urinary mutagenicity. Urine of 2 mechanics appeared to contain rather high levels of XAD-7 mutagens, but in view of the uneven distribution over the different collection periods any relationship with the exposure to diesel exhaust mutagens seems improbable. Degree and frequency of faecal mutagenicity was higher in office workers than in mechanics. The pattern of faecal mutagenicity was characteristic of that of faecapentaenes. Statistical analysis did not reveal any consistent relationships between urinary and faecal mutagenicity and the various dietary variables. 相似文献
15.
Nitroarenes are ubiquitous environmental pollutants displaying potent genotoxicity in bacterial and mammalian cells. In this study, 2,4,7-trinitro-9-fluorenone (TNF) was more potent than 1-nitropyrene (1-NP) in eliciting genotoxic responses in 4 mammalian cell lines. All 4 cell types were capable of activating the nitroarenes, since no special incubation conditions were required. Inhibition of normal DNA synthesis and cytotoxicity were significantly increased with TNF in a dose range of 0.2-5 micrograms/ml for human teratocarcinoma (PA1) cells, mouse Sertoli (TM4) cells, rat hepatoma (RL12) cells, and human-Chinese hamster ovary (CHO-K1) cells. For 1-NP, a dose range of 10-20 micrograms/ml was required to achieve comparable results for the respective cell lines. Only the RL12 and CHO-K1 cells showed recovery of normal DNA synthesis when TNF or 1-NP was removed from the medium. The other cell types showed little or no recovery up to 42 h after removal of the nitroarene. In exclusively studying TNF, the induction of sister-chromatid exchanges (SCEs) and a delay in cell cycle as monitored by harlequin chromosomes, were observed at a concentration range of 0.003-0.2 microgram/ml in PA1, TM4, and RL12 cells. In CHO-K1 cells, TNF at 0.001-1 microgram/ml was clearly mutagenic at the hprt locus. 相似文献
16.
M A McCartney B F Chatterjee E C McCoy E A Mortimer H S Rosenkranz 《Mutation research》1986,171(2-3):99-104
Organic solvent extracts from airplane emission particulates are mutagenic for Salmonella typhimurium strain TA98. Using Salmonella tester strains deficient in enzymes required for the bioactivation of various nitroarenes, the mutagenicity present in these emissions was ascribed to the presence of nitrated polycyclic aromatic hydrocarbons. Based on the known aircraft particulate emission rates at U.S. airports, and using 1-nitropyrene (1-NP) and 1,8-dinitropyrene (1,8-DNP) as surrogates, it is calculated that at a minimum 7 kg 1-NP and 20 g, 1,8-DNP are emitted daily at a typical U.S. airport. 相似文献
17.
Comparison of metabolic activation of carcinogens in human, rat, and hamster hepatocytes 总被引:1,自引:0,他引:1
The activities to activate and detoxify procarcinogens were compared in intact hepatocytes from humans, Sprague-Dawley rats and Syrian golden hamsters. Mutagenic metabolites that were released from the isolated hepatocytes were detected by mutation induction in co-cultivated Salmonella typhimurium TA98. Hepatocytes from the 3 animal species all activated aflatoxin B1 (AFB1), acetylaminofluorene (AAF) and aminofluorene (AF) and released active metabolites to induce mutation in the indicator S. typhimurium T98. Hamster hepatocytes were more effective than were human and rat hepatocytes to mediate mutation of Salmonella TA98 by AFB1, AAF and AF. Hepatocytes of human and rat failed to mediate mutation by 1-aminopyrene (1-AP). Indeed, at low concentration of 1-AP and 1-nitropyrene (1-NP), the presence of the hepatocytes decreased the number of TA98 revertants. Only at higher concentrations of 1-aminopyrene and 1-nitropyrene did hamster hepatocytes increase mutation frequencies of indicator cells over the control groups. It seems that hepatocytes, particularly human hepatocytes, are better able to absorb and detoxify 1-AP and 1-NP than to activate them. 相似文献
18.
The ability of the common aquatic contaminant 1-nitropyrene to form DNA adducts in fish was investigated in vitro and in vivo using Brown trout (Salmo trutta) and turbot (Scophthalmus maximus)in comparison to the Wistar rat. In vitro studies used Brown trout (control and induced (50 mg kg-1-naphthoflavone (NF), i.p. 3 day pre-treatment single injection)) and induced rat (PB; 0 1% w/v for 7 days in drinking water, NF; 80 mg kg-1, single injection 2 days prior to sacrifice). Hepatic 9000 g supernatant (S9 fractions) were incubated for 2 hours (at 25 C for fish and 37 C for rat) with calf thymus DNA (1mg) and 1-NP (100 M). With all S9 fractions the presence of three distinct 1-NP-related DNA adducts was detected using the butanol enrichment procedure of the 32Ppostlabelling assay. A greater level of DNA adducts was observed with the uninduced compared to the induced trout S9 (37, 12 and 8 fold greaterfor adducts in chromatograph areas 1-3 respectively) suggesting the enhancement of detoxification pathways with respect to bulky adducts following NF pre-treatment. DNA adduct levels in the induced rat consistently demonstrated approximately two-fold higher levels as compared to the induced fish, reflecting the lower protein levels in the S9 fraction of Brown trout (42 and 22 mg ml-1 for rat and fish respectively). Turbot, rat and Brown trout (uninduced and induced (NF; 50 mg kg-1; i.p. single injection 3 days prior)) were dosed with 100 mg kg-1 1-NP (i.p. single injection, 24 hours). Liver DNA from both turbot and rat exhibited a 1- NP related adduct spot which was similar in position to that of area 1 in the incubations with S9 from rat and Brown trout. However, in contrast to the in vitro studies no 1-NPrelated adducts were found in liver DNA from induced and uninduced Brown trout. This study highlights the potential, in a marine and a freshwater fish, for 1-NP metabolism to reactive of binding to DNA. However, activation of 1-NP was more optimal in the S9-mediated system, possibly reflecting the influence of detoxification systems. 相似文献
19.
Nitropyrenes are inducers of polyoma viral DNA synthesis 总被引:1,自引:0,他引:1
The biological activity of a series of nitropyrenes was assayed by measuring their ability to induce the asynchronous replication of viral DNA in rat fibroblasts transformed by a ts-a mutant of polyoma virus. Concentrations of 10-30 micrograms/ml of 1-nitropyrene (1-NP) induced viral replication, and this effect was enhanced by addition of rat-liver S9 microsomal fraction (300 micrograms/ml) to the culture medium. The response was less than that obtained with 0.1 micrograms/ml of the activated metabolite of benzo[a]pyrene (BP), BP trans-7,8-dihydrodiol-9,10 epoxide (anti) (BPDE). A series of di-, tri-, and tetra-nitropyrenes were also found to induce polyoma DNA replication, in the absence of exogenous microsomal activation, displaying strongly positive effects at 0.5-2.0 microgram/ml. Dose-response curves with 1,6-dinitropyrene (1,6-DNP) from 0.01 to 0.5 microgram/ml indicated that this compound was approximately equipotent with BPDE for induction of polyoma DNA synthesis. Studies of drug metabolism, DNA binding and DNA adduct formation indicate that 1,6-DNP is metabolized in this cell line, binds to DNA, and forms stable adducts. The level of DNA modification seen with 1,6-DNP is higher than that observed under comparable conditions with an equivalent dose of BPDE. These findings provide additional evidence that the nitropyrene class of compounds can exert biological effects in mammalian cells, and that the dinitropyrenes are more potent than 1-NP. 相似文献
20.