Evidence that 4‐aminobiphenyl, benzidine, and benzidine congeners produce genotoxicity through reactive oxygen species

Makena, Patrudu S.; Chung, King‐Thom

doi:10.1002/em.20288

Cited by 38 publications

(23 citation statements)

References 38 publications

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“…4,25 In vitro, N–OH-ABP ( N -hydroxyl-ABP) produces hydrogen peroxide and oxidizes DNA in the presence of Cu 2+ ions and NADPH (Scheme 5). 23,39 …”

Section: Resultsmentioning

confidence: 99%

Evaluating Metabolite-Related DNA Oxidation and Adduct Damage from Aryl Amines Using a Microfluidic ECL Array

Bist¹,

Bhakta²,

Jiang³

et al. 2017

Anal. Chem.

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Damage to DNA from the metabolites of drugs and pollutants constitutes a major human toxicity pathway known as genotoxicity. Metabolites can react with metal ions and NADPH to oxidize DNA or participate in SN2 reactions to form covalently linked adducts with DNA bases. Guanines are the main DNA oxidation sites, and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) is the initial product. Here we describe a novel electrochemiluminescent (ECL) microwell array that produces metabolites from test compounds and measures relative rates of DNA oxidation and DNA adduct damage. In this new array, films of DNA, metabolic enzymes, and an ECL metallopolymer or complex assembled in microwells on a pyrolytic graphite wafer are housed in dual microfluidic chambers. As reactant solution passes over the wells, metabolites form and can react with DNA in the films to form DNA adducts. These adducts are detected by ECL from a RuPVP polymer that uses DNA as a coreactant. Aryl amines also combine with Cu2+ and NADPH to form reactive oxygen species (ROS) that oxidize DNA. The resulting 8-oxodG was detected selectively by ECL-generating bis(2,2′-bipyridine)-(4-(1,10-phenanthrolin-6-yl)-benzoic acid)Os(II). DNA/enzyme films on magnetic beads were oxidized similarly, and 8-oxodG determined by LC/MS/MS enabled array standardization. The array limit of detection for oxidation was 720 8-oxodG per 106 nucleobases. For a series of aryl amines, metabolite-generated DNA oxidation and adduct formation turnover rates from the array correlated very well with rodent 1/TD50 and Comet assay results.

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“…4,25 In vitro, N–OH-ABP ( N -hydroxyl-ABP) produces hydrogen peroxide and oxidizes DNA in the presence of Cu 2+ ions and NADPH (Scheme 5). 23,39 …”

Section: Resultsmentioning

confidence: 99%

Evaluating Metabolite-Related DNA Oxidation and Adduct Damage from Aryl Amines Using a Microfluidic ECL Array

Bist¹,

Bhakta²,

Jiang³

et al. 2017

Anal. Chem.

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“…There are many research papers on the genotoxicity of DCB in vivo and in vitro. In the in vitro assays, DCB was mutagenic in Salmonella typhimurium [Makena and Chung, ], increased the frequency of sister chromatid exchange [Ohe et al, ], and produced unscheduled DNA synthesis and single‐strand DNA breaks in human cells [Chen et al, ]. In the in vivo assay, DCB increased the frequency of micronuclei [Čihák and Vontorková, ] and chromosomal aberrations in bone marrow cells [You et al, ] and increased unscheduled DNA synthesis in the livers of rats [Čihák and Vontorková, ].…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of 3,3′‐dichlorobenzidine‐mediated toxicity in HepG2 cells

Chen

Tuan

et al. 2014

Environ and Mol Mutagen

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3,3'-Dichlorobenzidine (DCB) (CAS 91-94-1), a synthetic, chlorinated, primary aromatic amine, is typically used as an intermediate in the manufacturing of pigments for printing inks, textiles, paints, and plastics. In this study, we found that DCB could significantly inhibit the cell viability of HepG2 cells in a concentration-dependent manner. Flow cytometry revealed that DCB induced G2/M-phase arrest and apoptosis in HepG2 cells. DCB treatment dramatically induced the dissipation of mitochondrial membrane potential (Δψm ) and enhanced the enzymatic activities of caspase-9 and caspase-3 whilst hardly affecting caspase-8 activity. Furthermore, Western blotting indicated that DCB-induced apoptosis was accompanied by the down-regulation of Bcl-2/Bax ratio. These results suggested that DCB led to cytotoxicity involving activation of mitochondrial-dependent apoptosis through Bax/Bcl-2 pathways in HepG2 cells. Furthermore, HepG2 cells treated with DCB showed significant DNA damage as supported by the concentration-dependent increase in olive tail moments as determined by the comet assay and by concentration- and time-dependent increase in histone H2AX phosphorylation (γ-H2AX). Two-dimensional-difference gel electrophoresis (2D-DIGE), combined with mass spectrometry (MS), was used to unveil the differences in protein expression between cells exposed to 25 µM or 100 µM of DCB for 24 hr and the control cells. Twenty-seven differentially expressed proteins involved in DNA repair, unfolded protein response, metabolism, cell signaling, and apoptosis were identified. Among these, 14-3-3 theta, CGI-46, and heat-shock 70 protein 4 were confirmed using Western blot assay. Taken together, these data suggest that DCB is capable of inducing DNA damage and some cellular stress responses in HepG2 cells, thus eventually leading to cell death by apoptosis.

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“…Benzidine in this model was converted by horseradish peroxidase in the presence of H 2 O 2 into a primary cation-radical, further oxidation of which produced a monoprotonated diimine [5]. The oxidation product reacted with DNA purines and eventually formed cross links in the biomolecule.…”

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confidence: 99%

“…The DNA-protector activity of the lignans was assessed using a model for DNA damage by peroxidase oxidation products of benzidine, which is an indirect action carcinogen [4][5][6]. Benzidine in this model was converted by horseradish peroxidase in the presence of H 2 O 2 into a primary cation-radical, further oxidation of which produced a monoprotonated diimine [5].…”

mentioning

confidence: 99%

DNA-protector and cytotoxic activity of secoisolariciresinol diglucoside derivatives

Stasevich¹,

Шман

Mikhalenok³

et al. 2010

Chem Nat Compd

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The relationship between the chemical structure and DNA-protector and cytotoxic activities of phenylpropane lignans was studied. Analogs were synthesized from the lignan secoisolariciresinol diglucoside (SDG) isolated from Linum usitatissimum seeds. It was shown that SDG derivatives secoisolariciresinol and secoisolariciresinol-4c,4s-diacetate, which were not glucosides, exhibited greater cytotoxic activity in vitro than the starting lignan. The cytotoxicity was slightly elevated upon acetylation of the aglycon phenol hydroxyls whereas the DNA-protector activity decreased substantially. The DNA-protector activity of the derivative without the carbohydrate was slightly greater than that of the starting SDG. This was explained by binding of free radicals by the butanediol hydroxyls. It was proposed that the activity of the cytotoxic derivatives was mediated by induction of apoptosis of the tumor cells.Lignans are natural biologically active compounds that consist of two phenylpropane units joined by a E-Ec-bond. Many representatives of this class exhibit antioxidant and antitumor properties [1]. Natural lignans are also interesting because of their ability to be used as templates for designing drugs with various biological activities (antitumor, antiviral, antifungal) [2]. Clear examples of medicines based on natural lignan are podophyllotoxin and its derivatives, the antitumor drugs etoposide and teniposide [2].Herein we report results from a study of the relationship between the chemical structure and biological activity of phenylpropane lignans that were synthesized from secoisolariciresinol diglucoside (SDG) isolated from seeds of Linum isutatissimum. We investigated the relationship of the DNA-protector and cytotoxic activity of the natural lignan SDG (1) and its derivatives to the chemical structure.

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Evidence that 4‐aminobiphenyl, benzidine, and benzidine congeners produce genotoxicity through reactive oxygen species

Cited by 38 publications

References 38 publications

Evaluating Metabolite-Related DNA Oxidation and Adduct Damage from Aryl Amines Using a Microfluidic ECL Array

Evaluating Metabolite-Related DNA Oxidation and Adduct Damage from Aryl Amines Using a Microfluidic ECL Array

Molecular mechanisms of 3,3′‐dichlorobenzidine‐mediated toxicity in HepG2 cells

DNA-protector and cytotoxic activity of secoisolariciresinol diglucoside derivatives

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