SHORT COMMUNICATION: Detection of DNA adducts in the white blood cells of B6C3F1 mice treated with benzene
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We have employed the P1-enhanced 32P-postlabeling procedure to detect the formation DNA of adducts in the white blood cells (WBC) of B6C3F1 mice treated by i.p. injection with benzene. Treatment twice a day with 440 mg/kg benzene for 1–7 days resulted in the formation of one major (adduct 1) and one minor (adduct 2) DNA adduct in the WBCs of mice. The same DNA adduct pattern was also found in the bone marrow (BM) of benzene treated mice. The relative adduct levels were dependent upon both benzene dose from 100–440 mg/kg and treatment time from 1 to 7 days. The relative adduct levels ranged between 0.11 and 1.33 adducts in 107 nucleotides for WBCs and 0.16–1.21 adducts in 107 nucleotides for BM. Following treatment with benzene, the levels of DNA adducts formed in WBCs were significantly correlated with the levels of DNA adducts formed in BM (r2 = 0.97, P <0.001). Our results suggest that measurement of DNA adducts in WBCs may be an indicator of DNA adduct formation in BM following BZ exposure.Keywords:
White (mutation)
Abstract N-Heterocyclic aromatics are environmental carcinogenic pollutants. Of these compounds, 7H-dibenzo[c,g]carbazole (DBC) is a liver and skin carcinogen in the mouse by topical application and a lung carcinogen by IP injection, whereas dibenz[a,j]acridine (DBA) is a skin carcinogen by topical application. Using 32P-postlabeling techniques, it was found that DBC-DNA adduct 6 is the major adduct in the liver, consistent with the metabolism of DBC to the 3-OH-DBC; adducts 2 and 3 are major adducts in the skin and adduct 3 is the major adduct in the lung. On the other hand, DBA adduction is apparent only in the skin and is consistent with the initial metabolism to DBA-3, 4-dihydrodiol. These data indicate that the adduct pattern, as well as the proximate metabolites, are target organ specific; these data will have an impact on the development of biomarkers of the carcinogenic process.
dBc
Acridine
Deoxyguanosine
DNA adduct
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Abstract Limited sensitivity of existing assays has prevented investigation of whether Adriamycin–DNA adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin–DNA adducts/104 bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin–DNA adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We have used conditions previously validated (by less sensitive decay counting) to extract [14C]Adriamycin–DNA adducts from cells and adapted the methodology to AMS detection. Here we show the first direct evidence of Adriamycin–DNA adducts at clinically-relevant Adriamycin concentrations. [14C]Adriamycin treatment (25 nM) resulted in 4.4 ± 1.0 adducts/107 bp (∼1300 adducts/cell) in MCF-7 breast cancer cells, representing the best sensitivity and precision reported to date for the covalent binding of Adriamycin to DNA. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin–DNA adduct detection and revealed adduct formation within an hour of drug treatment. This method has been shown to be highly reproducible for the measurement of Adriamycin–DNA adducts in tumour cells in culture and can now be applied to the detection of these adducts in human tissues.
Accelerator mass spectrometry
DNA adduct
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In order to elucidate the chemistry involved in thiourea adduct formation, a new promising separation of 2, 6-dialkylnaphthalenes, the inclusion complex type of the thiourea adduct with mixture of dialkylnaphthalenes was studied using a powder X-ray diffraction method. A simple XRD pattern of both diethylnaphthalene (DEN) mixture-thiourea adduct and 2, 6-DEN-thiourea adduct was observed. Peaks that appeared in the XRD pattern of the former, gave diffraction angles different from those of the latter. XRD peaks of the thiourea adduct with the mixture of 2, 6-DEN and 2, 6-diisopropylnaphthalene (DIPN) gave angles and intensities both different from those of 2, 6-DEN-thiourea adduct and 2, 6-DIPN-thiourea adduct. The results indicate that the adduct consists of a single solid inclusion complex in which more reactive dialkylnaphthalnenes (2, 6-DEN, 2, 7-DEN, 2, 6-DIPN) are locked within like a solid solution. The expression of the equilibrium constant for the relevant adduct is also discussed.
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Reactive oxygen species can give rise to numerous modifications of DNA. We have investigated the formation of such modifications using the nuclease P1 digestion method of the 32P-postlabelling procedure for the detection of DNA damage. Analysis of DNA that had been treated with a Fenton-type system of copper (or iron) ions and H2O2 resulted in the detection of up to ten discrete 32P-labelled spots, displaying chromatographic characteristics similar to aromatic adducts, on PEI-cellulose TLC. Maximum total levels equivalent to 28 adducts/10(8) nucleotides were achieved after 15 min of treatment with Cu2+/H2O2. The formation of adducts was 1.5 times greater if single-stranded rather than double-stranded DNA was employed, suggesting an intrastrand effect. Experiments with 3'-deoxyribonucleotides demonstrated that the adducts detected did not represent base modifications such as 8-hydroxydeoxyguanosine or thymidine glycols. However, treatment of specific dinucleotides (dApdG and dApdA) was found to produce two major adducts that were chromatographically identical by TLC and HPLC to the two major adducts formed in DNA. It is proposed that these species with aromatic adduct-like characteristics are the result of the intrastrand linking of specific adjacent bases in DNA.
Hydroxyl radical
Characterization
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From December 2016 to December 2017, the concentrations of the benzene series (benzene, toluene, xylene, and ethyl-benzene) in air were analyzed in 223 residential buildings in five climatic regions of China during different seasons. The arithmetic average concentrations of benzene, toluene, xylene, and ethyl-benzene were 6.78, 17.4, 17.68, and 9.87 μg·m-3, respectively. Indoor benzene series concentrations in China were slightly higher than that in other countries; the standard limits for indoor benzene series concentrations in China are much higher than those of other countries and organizations. Among the many factors affecting the concentration of the benzene series in the rooms, the relationship between the completion time of decoration, smoking, and cooking frequency and the concentration of benzene homologues was studied. The results showed that the concentration of toluene decreased with the prolongation of decoration time, the concentration of benzene in smoking households was higher than that in non-smoking families, and there was no direct correlation between cooking frequency and indoor concentration of the benzene series. The study provides statistical data on exposure to the benzene series in decorated homes and a discussion of setting values of relevant standards.
Indoor air
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3-methyllumiflavin, irradiated in the first flavin band, forms a N-5 adduct in pyridine solutions. The possible nature of this adduct is discussed, together with the effect of water on the course of the photoreduction reaction.
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Abstract Hexamethylphosphorus triamide has been allowed to react with p,p′-dinitrobenzil, p-chlorobenzil, p,p′-difluorobenzil, p,p′-dimethylbenzil and p,p′-dimethoxybenzil. All of these materials in benzene-d6 had negative δ 31P chemical shifts except for the p,p′-dinitro adduct whose resonance was found at δ + 17.6. In dichloromethane-d2 the resonances ranged from δ + 38.2 for the p,p′-dinitro adduct to δ − 22.5 for the p,p′-dimethoxy adduct. The 13C NMR spectra of these compounds all showed coupling J POCC to the ipso carbons except for the p,p′-dinitro adduct. These data indicate that the p,p′-dinitro adduct is ionizing rapidly and that the others are phosphoranes. On cooling the coupling was lost for the p,p′-difluoro adduct and for the p-chloro adduct. These spectral changes are attributed to rapid ionization which occurs because of the change of the dielectric constant with change in temperature.
Dichloromethane
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Abstract Unlike 1,2,5‐triphenylphosphole, 3‐butyl‐1,2‐diphenylphosphindole reacts smoothly with two molecules of dimethyl acetylenedicarboxylate to give the phosphindole oxide, a yellow adduct and a colourless adduct. The case of the reaction is taken to indicate less lone pair interaction with the π‐system in phosphindoles than in phospholes. The yellow adduct is shown to be a phosphindolium cyclopentadienylide, i.e. an adduct of the phosphindole and two molecules of the ester less one oxygen atom. The colourless adduct is shown to be a 1:2:1 adduct of the phosphindole, the ester and water and has a benzodihydrophosphonin structure. Mechanisms for the formation of both adducts are proposed. Adducts of this general type were previously unknown in organophosphorus chemistry.
Dimethyl acetylenedicarboxylate
Lone pair
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