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Santhanam Swaminathan – One of the best experts on this subject based on the ideXlab platform.

  • Identification of N-(deoxyguanosin-8-yl)-4-azobiphenyl by 32P-postlabeling analyses of DNA in human uroepithelial cells exposed to proximate metabolites of the environmental carcinogen 4-Aminobiphenyl
    Environmental and molecular mutagenesis, 2002
    Co-Authors: James F. Hatcher, Santhanam Swaminathan

    Abstract:

    DNA adducts formed in human uroepithelial cells (HUC) following exposure to N-hydroxy-4-Aminobiphenyl (N-OH-ABP), the proximate metabolite of the human bladder carcinogen 4-Aminobiphenyl (ABP), were analyzed by the 32P-postlabeling method. Two adducts detected by 32P-postlabeling were previously identified as the 3′,5′-bisphospho derivatives of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl (dG-C8-ABP) and N-(deoxyadenosin-8-yl)-4-Aminobiphenyl (dA-C8-ABP) (Frederickson S et al. [1992] Carcinogenesis 13: 955–961; Hatcher and Swaminathan [1995b] Carcinogenesis 16: 295–301). In contrast to the dG-C8-ABP adduct, which was 3′-dephosphorylated by nuclease P1, dA-C8-ABP was resistant to nuclease P1, thus providing an enrichment step before postlabeling. Autoradiography of the two-dimensional thin-layer chromatogram of the postlabeled products obtained following nuclease P1 digestion revealed several minor adducts, one of which has been identified in the present study. Postlabeling analyses following nuclease P1 digestion of the products obtained from the reaction of N-acetoxy-4-Aminobiphenyl with deoxyguanosine-3′-monophosphate (dGp) demonstrated the presence of this minor adduct. The 3′-monophosphate derivative of the adduct was subsequently chromatographically purified and subjected to spectroscopic analyses. Based on proton NMR and mass spectroscopic analyses of the synthetic product, the chemical structure of the adduct has been identified as N-(deoxyguanosin-N2-yl)-4-azobiphenyl (dG-NN-ABP). 32P-Postlabeling analysis of the nuclease P1–enriched DNA hydrolysate of HUCs treated with N-OH-ABP or N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) showed the presence of the dG-NN-ABP adduct. It was also detected in calf thymus DNA incubated with HUC cytosol and N-OH-ABP in the presence of acetyl-CoA, or incubated with HUC microsomes and N-OH-AABP. These results demonstrate that in the target cells for ABP carcinogenesis in vivo, N-OH-ABP and N-OH-AABP are bioactivated by acyltransferases to reactive arylnitrenium ions that covalently interact at the N2 position of deoxyguanosine in DNA. Environ. Mol. Mutagen. 39:314–322, 2002. © 2002 Wiley-Liss, Inc.

  • Identification of new DNA adducts in human bladder epithelia exposed to the proximate metabolite of 4-Aminobiphenyl using 32P-postlabeling method
    Chemico-biological interactions, 2002
    Co-Authors: Santhanam Swaminathan, James F. Hatcher

    Abstract:

    The DNA adducts were analyzed by 32P-postlabeling method following exposure of human uroepithelial cells (HUC) to N-hydroxy-4-Aminobiphenyl (N-OH-ABP), the proximate metabolite of the human bladder carcinogen 4-Aminobiphenyl (ABP). TLC of the postlabeled products on the first dimension revealed several products, the majority of which stayed close to the origin and were earlier identified as the 3′,5′ -bisphospho derivatives of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl and N-(deoxyadenosin-8-yl)-4-Aminobiphenyl (Carcinogenesis 13 (1993) 955; Carcinogenesis 16 (1995) 295). Here we report characterization of two additional adducts that amounted to less than 5% of the total adducts. Autoradiography of D1 chromatogram of the postlabeled products of calf thymus DNA chemically interacted with N-OH-ABP under acidic conditions revealed two adducts, #1 and #2, with R(f) values of about 0.2 and 0.3, respectively. Two adducts with D1 thin layer chromatographic properties similar to those of adducts #1 and #2 were obtained on postlabeling analyses of products generated by chemical interaction of N-acetoxy-4-Aminobiphenyl (N-OAc-ABP) with deoxyguanosine-3′ -monophosphate (dGp). Based on proton NMR and mass spectroscopic analyses of the synthetic products derived from N-OAc-ABP, the chemical structures of adducts #1 and #2 have been identified as 3-(deoxyguanosin-N(2)-yl)-4-Aminobiphenyl, and N-(deoxyguanosin-N(2)-yl)-4-Aminobiphenyl, respectively. Both of these adducts were insensitive to digestion with nuclease P1. 32P-Postlabeling analysis of the nuclease P1 enriched DNA hydrolysate of HUC cells treated with N-OH-ABP showed the presence of adduct #2 but not adduct #1. Adduct #2 was also detected in calf thymus DNA incubated with HUC cytosol and N-OH-ABP in the presence of acetyl CoA. These results suggest that in the target cells for ABP carcinogenesis in vivo, N-OH-ABP is bioactivated by acetyl CoA-dependent acyltransferases to reactive arylnitrenium ions that covalently interact at N(2)-position of deoxyguanosine in DNA.

  • Detection of deoxyadenosine-4-Aminobiphenyl adduct in DNA of human uroepithelial cells treated with N-hydroxy-4-Aminobiphenyl following nuclease P1 enrichment and 32P-postlabeling analysis.
    Carcinogenesis, 1995
    Co-Authors: James F. Hatcher, Santhanam Swaminathan

    Abstract:

    To characterize the DNA adducts in human uroepithelial cells (HUC) exposed to 4-Aminobiphenyl and its proximate N-hydroxy metabolites, we used 32 P-postlabeling analyses following butanol extraction of the DNA hydrolysates. Using this method, we identified N-(deoxyguanosin-3′,5′-bisphospho-8-yl)-4-Aminobiphenyl (pdGp-ABP) as a major adduct and N-(deoxyadenosin-3′,5′-bisphospho-8-yl)-4-Aminobiphenyl (pdAp-ABP) as a minor adduct in an immortalized non-tumorigenic cell line of HUC following exposure to N-hydroxy-4-Aminobiphenyl (N-OH-ABP). Towards characterization of pdAp-ABP, we postlabeled the synthetic N-(deoxyadenosin-3′-phospho-8-yl)-4-Aminobiphenyl (dAp-ABP) adduct to generate pdAp-ABP and determined its chromatographic (TLC and HPLC) properties and sensitivity to nuclease P1 digestion. In contrast to pdGp-ABP, which was cleaved to the corresponding 5′-monophosphate by nuclease P1, the pdAp-ABP adduct was unaffected when incubated with nuclease P1 under similar conditions. To test whether nuclease P1 digestion could be adopted for enrichment of the dAp-ABP adduct in HUC samples, postlabeling analyses were carried out after butanol extraction following nuclease P1 digestion of the DNA hydrolysate. Under these conditions, the pdAp-ABP adduct was detected in DNA from HUC E7 cells treated with N-OH-ABP and in calf thymus DNA reacted with N-OH-ABP under acidic (pH 5.0) conditions. These data indicate that pdGp-ABP and pdAp-ABP adducts are generated in HUC E7 on treatment with N-OH-ABP and that nuclease P1 enrichment may provide a method for qualitative and quantitative analyses of the pdAp-ABP adduct in DNA

James F. Hatcher – One of the best experts on this subject based on the ideXlab platform.

  • Identification of N-(deoxyguanosin-8-yl)-4-azobiphenyl by 32P-postlabeling analyses of DNA in human uroepithelial cells exposed to proximate metabolites of the environmental carcinogen 4-Aminobiphenyl
    Environmental and molecular mutagenesis, 2002
    Co-Authors: James F. Hatcher, Santhanam Swaminathan

    Abstract:

    DNA adducts formed in human uroepithelial cells (HUC) following exposure to N-hydroxy-4-Aminobiphenyl (N-OH-ABP), the proximate metabolite of the human bladder carcinogen 4-Aminobiphenyl (ABP), were analyzed by the 32P-postlabeling method. Two adducts detected by 32P-postlabeling were previously identified as the 3′,5′-bisphospho derivatives of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl (dG-C8-ABP) and N-(deoxyadenosin-8-yl)-4-Aminobiphenyl (dA-C8-ABP) (Frederickson S et al. [1992] Carcinogenesis 13: 955–961; Hatcher and Swaminathan [1995b] Carcinogenesis 16: 295–301). In contrast to the dG-C8-ABP adduct, which was 3′-dephosphorylated by nuclease P1, dA-C8-ABP was resistant to nuclease P1, thus providing an enrichment step before postlabeling. Autoradiography of the two-dimensional thin-layer chromatogram of the postlabeled products obtained following nuclease P1 digestion revealed several minor adducts, one of which has been identified in the present study. Postlabeling analyses following nuclease P1 digestion of the products obtained from the reaction of N-acetoxy-4-Aminobiphenyl with deoxyguanosine-3′-monophosphate (dGp) demonstrated the presence of this minor adduct. The 3′-monophosphate derivative of the adduct was subsequently chromatographically purified and subjected to spectroscopic analyses. Based on proton NMR and mass spectroscopic analyses of the synthetic product, the chemical structure of the adduct has been identified as N-(deoxyguanosin-N2-yl)-4-azobiphenyl (dG-NN-ABP). 32P-Postlabeling analysis of the nuclease P1–enriched DNA hydrolysate of HUCs treated with N-OH-ABP or N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) showed the presence of the dG-NN-ABP adduct. It was also detected in calf thymus DNA incubated with HUC cytosol and N-OH-ABP in the presence of acetyl-CoA, or incubated with HUC microsomes and N-OH-AABP. These results demonstrate that in the target cells for ABP carcinogenesis in vivo, N-OH-ABP and N-OH-AABP are bioactivated by acyltransferases to reactive arylnitrenium ions that covalently interact at the N2 position of deoxyguanosine in DNA. Environ. Mol. Mutagen. 39:314–322, 2002. © 2002 Wiley-Liss, Inc.

  • Identification of new DNA adducts in human bladder epithelia exposed to the proximate metabolite of 4-Aminobiphenyl using 32P-postlabeling method
    Chemico-biological interactions, 2002
    Co-Authors: Santhanam Swaminathan, James F. Hatcher

    Abstract:

    The DNA adducts were analyzed by 32P-postlabeling method following exposure of human uroepithelial cells (HUC) to N-hydroxy-4-Aminobiphenyl (N-OH-ABP), the proximate metabolite of the human bladder carcinogen 4-Aminobiphenyl (ABP). TLC of the postlabeled products on the first dimension revealed several products, the majority of which stayed close to the origin and were earlier identified as the 3′,5′ -bisphospho derivatives of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl and N-(deoxyadenosin-8-yl)-4-Aminobiphenyl (Carcinogenesis 13 (1993) 955; Carcinogenesis 16 (1995) 295). Here we report characterization of two additional adducts that amounted to less than 5% of the total adducts. Autoradiography of D1 chromatogram of the postlabeled products of calf thymus DNA chemically interacted with N-OH-ABP under acidic conditions revealed two adducts, #1 and #2, with R(f) values of about 0.2 and 0.3, respectively. Two adducts with D1 thin layer chromatographic properties similar to those of adducts #1 and #2 were obtained on postlabeling analyses of products generated by chemical interaction of N-acetoxy-4-Aminobiphenyl (N-OAc-ABP) with deoxyguanosine-3′ -monophosphate (dGp). Based on proton NMR and mass spectroscopic analyses of the synthetic products derived from N-OAc-ABP, the chemical structures of adducts #1 and #2 have been identified as 3-(deoxyguanosin-N(2)-yl)-4-Aminobiphenyl, and N-(deoxyguanosin-N(2)-yl)-4-Aminobiphenyl, respectively. Both of these adducts were insensitive to digestion with nuclease P1. 32P-Postlabeling analysis of the nuclease P1 enriched DNA hydrolysate of HUC cells treated with N-OH-ABP showed the presence of adduct #2 but not adduct #1. Adduct #2 was also detected in calf thymus DNA incubated with HUC cytosol and N-OH-ABP in the presence of acetyl CoA. These results suggest that in the target cells for ABP carcinogenesis in vivo, N-OH-ABP is bioactivated by acetyl CoA-dependent acyltransferases to reactive arylnitrenium ions that covalently interact at N(2)-position of deoxyguanosine in DNA.

  • Detection of deoxyadenosine-4-Aminobiphenyl adduct in DNA of human uroepithelial cells treated with N-hydroxy-4-Aminobiphenyl following nuclease P1 enrichment and 32P-postlabeling analysis.
    Carcinogenesis, 1995
    Co-Authors: James F. Hatcher, Santhanam Swaminathan

    Abstract:

    To characterize the DNA adducts in human uroepithelial cells (HUC) exposed to 4-Aminobiphenyl and its proximate N-hydroxy metabolites, we used 32 P-postlabeling analyses following butanol extraction of the DNA hydrolysates. Using this method, we identified N-(deoxyguanosin-3′,5′-bisphospho-8-yl)-4-Aminobiphenyl (pdGp-ABP) as a major adduct and N-(deoxyadenosin-3′,5′-bisphospho-8-yl)-4-Aminobiphenyl (pdAp-ABP) as a minor adduct in an immortalized non-tumorigenic cell line of HUC following exposure to N-hydroxy-4-Aminobiphenyl (N-OH-ABP). Towards characterization of pdAp-ABP, we postlabeled the synthetic N-(deoxyadenosin-3′-phospho-8-yl)-4-Aminobiphenyl (dAp-ABP) adduct to generate pdAp-ABP and determined its chromatographic (TLC and HPLC) properties and sensitivity to nuclease P1 digestion. In contrast to pdGp-ABP, which was cleaved to the corresponding 5′-monophosphate by nuclease P1, the pdAp-ABP adduct was unaffected when incubated with nuclease P1 under similar conditions. To test whether nuclease P1 digestion could be adopted for enrichment of the dAp-ABP adduct in HUC samples, postlabeling analyses were carried out after butanol extraction following nuclease P1 digestion of the DNA hydrolysate. Under these conditions, the pdAp-ABP adduct was detected in DNA from HUC E7 cells treated with N-OH-ABP and in calf thymus DNA reacted with N-OH-ABP under acidic (pH 5.0) conditions. These data indicate that pdGp-ABP and pdAp-ABP adducts are generated in HUC E7 on treatment with N-OH-ABP and that nuclease P1 enrichment may provide a method for qualitative and quantitative analyses of the pdAp-ABP adduct in DNA

Paul Vouros – One of the best experts on this subject based on the ideXlab platform.

  • Recent technical and biological development in the analysis of biomarker N-deoxyguanosine-C8-4-Aminobiphenyl.
    Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2018
    Co-Authors: Zhidan Chen, Yuesheng Zhang, Paul Vouros

    Abstract:

    4-Aminobiphenyl (4-ABP) which is primarily formed during tobacco combustion and overheated meat is a major carcinogen responsible for various cancers. Its adducted form, N-deoxyguanosine-C8-4-Aminobiphenyl (dG-C8-4-ABP), has long been employed as a biomarker for assessment of the risk for cancer. In this review, the metabolism and carcinogenisity of 4-ABP will be discussed, followed by a discussion of the current common approaches of analyzing dG-C8-4-ABP. The major part of this review will be on the history and recent development of key methods for detection and quantitation of dG-C8-4-ABP in complex biological samples and their biological applications, from the traditional 2P-postlabelling and immunoassay methods to modern liquid chromatography-mass spectrometry (LC-MS) with the latter as the focus. Many vital biological discoveries based on dG-C8-4-ABP have been published by using the nanoLC-MS with column switching platform in our laboratory, which has also been adopted and further improved by many other researchers. We hope this review can provide a perspective of the challenges that had to be addressed in reaching our present goals and possibly bring new ideas for those who are still working on the frontline of DNA adducts area.

  • Quantification of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl adducts in human lymphoblastoid TK6 cells dosed with N-hydroxy-4-acetylaminobiphenyl and their relationship to mutation, toxicity, and gene expression profiling.
    Analytical chemistry, 2006
    Co-Authors: Elaine M. Ricicki, Wen Luo, Wenhong Fan, Lue Ping Zhao, Helmut Zarbl, Paul Vouros

    Abstract:

    Gene expression profiles that are anchored to phenotypic endpoints may lead to the identification of signatures that predict mutagenicity or carcinogenicity. The study presented here describes the analysis of DNA adducts in the human TK6 lymphoblastoid cell line after exposure to N-hydroxy-4-Aminobiphenyl, a mutagenic metabolite of 4-Aminobiphenyl. A validated nano-LC microelectrospray mass spectrometry assay is reported for the detection and quantification of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl (dG-C8-ABP), the principal DNA adduct of 4-Aminobiphenyl. Limits of quantification, based on a signal-to-noise ratio of 10:1, are determined to correspond to approximately 27 fg of dG-C8-ABP injected on-column. The assay has been used to measure the steady-state levels of the adduct in the human TK6 lymphoblastoid cell line as a function of dose (0.5, 1.0, and 10.0 microM) and time (2, 6, and 27 h) after exposure to N-hydroxy-4-Aminobiphenyl. The levels of dG-C8-ABP adducts in the cells, ranging from 18 to 500 adducts in 10(9) nucleotides, were then correlated to cell toxicity, induced mutation at the TK (thymidine kinase) and HPRT loci, and gene expression profiling through microarray analysis. Cell cultures were evaluated for toxicity by growth curve extrapolation, mutation assays were performed on the HPRT and TK loci, and gene expression profiles were generated by analyses using microarray technology. In the mutation assay analysis, as the toxicant concentration increased, there was an increase in mutation fraction, indicating a direct correlation to metabolite dosing level and mutations occurring at these two loci. Statistical analysis of the gene expression data determined that a total of 2250 genes exhibited statistically significant changes in expression after treatment with N-OH-AABP (P < 0.05). Among the genes identified, 2245 were up-regulated, whereas 5 genes that had functions in cell survival and cell growth and, hence, could be indicators of toxicity, were down-regulated relative to controls. The results demonstrate the value of anchoring gene expression patterns to phenotypic markers, such as DNA adduct levels, toxicity, and mutagenicity.

  • Detection and quantification of N-(deoxyguanosin-8-yl)-4-Aminobiphenyl adducts in human pancreas tissue using capillary liquid chromatography-microelectrospray mass spectrometry.
    Chemical research in toxicology, 2005
    Co-Authors: Elaine M. Ricicki, John R. Soglia, Candee H. Teitel, Robert Kane, And Fred Kadlubar, Paul Vouros

    Abstract:

    Cigarette smoking has been associated with various cancers including bladder and pancreas. 4-Aminobiphenyl has been isolated as a constituent of cigarette smoke and has been established as a carcinogen in various animal models and humans. In rodents and humans, 4-Aminobiphenyl is N-hydroxylated and forms adducts to DNA, the predominant one being N-(deoxyguanosin-8-yl)-4-Aminobiphenyl (dG-C8-ABP). In this study, we report a micro-electrospray mass spectrometric (μESI-MS) isotope dilution method for the detection and quantification of dG-C8-ABP in human pancreatic tissue. A reverse phase capillary column (320 μm ID) was connected to a triple quadrupole mass spectrometer via a commercially available micro-ESI source. The system was operated in the selected reaction monitoring mode transmitting the [M + H]+ → [M + H − 116]+ transitions for both the analyte and the isotopically labeled internal standard. Twelve human pancreas samples were analyzed, where six were current smokers (three male and three female) a…