3-Nitrobenzanthrone (3-NBA) induced micronucleus formation and DNA damage in human hepatoma (HepG2) cells

Lamy, Evelyn; Kassie, Fekadu; Gminski, Richard; Schmeiser, Heinz H.; Mersch-Sundermann, Volker

doi:10.1016/j.toxlet.2003.07.001

Cited by 60 publications

(47 citation statements)

References 28 publications

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“…Since HepG2 cells are not responsive to 1,6-and 1,8-dinitropyrene, which require reduction involving two electrons and acetylation for their genotoxicity, it was postulated that, in contrast to V79 cells, these cells do not possess these enzymes [Eddy et al, 1986;Roscher and Wiebel, 1991;Silvers et al, 1994]. However, heterocyclic amines and 3-nitrobenzanthrone, which require acetylation to produce DNA damage, induce micronuclei in HepG2 cells [Knasmüller et al, 1999;Kawanishi et al, 2000;Lamy et al, 2004] (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity of nitrosulfonic acids, nitrobenzoic acids, and nitrobenzylalcohols, pollutants commonly found in ground water near ammunition facilities

Grummt

Wunderlich

Chakraborty³

et al. 2006

Environ. Mol. Mutagen.

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2-Amino-4,6-dinitrobenzoic acid (2-A-4,6-DNBA), 4-amino-2,6-dinitrobenzoic acid (4-A-2,6-DNBA), 2,4,6-trinitrobenzoic acid (2,4,6-TNBA), 2-amino-4, 6-dinitrobenzylalcohol (2-A-4,6-DNBAlc), 4-amino-2,6-dinitrobenzylalcohol (4-A-2,6-DNBAlc), 2,4-dinitrotoluol-5-sulfonic acid (2,4-DNT-5-SA), 2,4-dinitrotoluol-3-sulfonic acid (2,4-DNT-3-SA), and 2, 4-dinitrobenzoic acid (2,4-DNBA) are derivatives of nitro-explosives that have been detected in groundwater close to munitions facilities. In the present study, the genotoxicity of these compounds was evaluated in Salmonella/microsome assays (in strains TA100 and TA98, with and without S9 and in TA98NR without S9), in chromosomal aberration (CA) tests with Chinese hamster fibroblasts (V79), and in micronucleus (MN) assays with human hepatoma (HepG2) cells. All compounds except the sulfonic acids were positive in the bacterial mutagenicity tests, with 2,4,6-TNBA producing the strongest response (8023 revertants/micromol in TA98 without S9 activation). 2-A-4,6-DNBA was a direct acting mutagen in TA98, but negative in TA100. The other positive compounds were approximately 1-3 orders of magnitude less mutagenic than 2,4,6-TNBA in TA98 and in TA100; relatively strong effects ( approximately 50-400 revertants/micromol) were produced by the benzylacohols in the two indicator strains. With the exception of 2,4-DNBA, the mutagenic responses were lower in the nitroreductase-deficient strain TA98NR than in the parental strain. 2,4-DNBA produced a marginally positive response in the V79-cell CA assay; the other substances were devoid of activity. Only the benzoic acids were tested for MN induction in HepG2 cells, and all produced positive responses. As in the bacterial assays, the strongest effect was seen with 2,4,6-TNBA (significant induction at >or=1.9 microM). 4-A-2,6-DNBA was positive at 432 microM; the weakest effect was observed with 2,4,-DNBA (positive at >or=920 microM). The differences in the sensitivity of the indicator cells to these agents can be explained by differences in the activities of enzymes involved in the activation of the compounds. The strong responses produced by some of the compounds in the human-derived cells suggest that environmental exposure to these breakdown products of nitro-explosives may pose a cancer risk in man.

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Section: Discussionmentioning

confidence: 99%

Genotoxicity of nitrosulfonic acids, nitrobenzoic acids, and nitrobenzylalcohols, pollutants commonly found in ground water near ammunition facilities

Grummt

Wunderlich

Chakraborty³

et al. 2006

Environ. Mol. Mutagen.

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“…3-NBA is a potent mutagen in the Ames Salmonella typhimurium assay (5) and in the transgenic Muta Mouse assay (9). It has been shown to be genotoxic in several short-term tests (10)(11)(12)(13)(14) and its genotoxicity has been further documented by the detection of specific DNA adducts formed in vitro as well as in vivo in rodents (9,10,12,(14)(15)(16)(17)(18)(19)(20). Moreover, preliminary data suggest that 3-NBA is carcinogenic to rats (21).…”

Section: Introductionmentioning

confidence: 99%

Environmental Pollutant and Potent Mutagen 3-Nitrobenzanthrone Forms DNA Adducts after Reduction by NAD(P)H:Quinone Oxidoreductase and Conjugation by Acetyltransferases and Sulfotransferases in Human Hepatic Cytosols

et al. 2005

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3-Nitrobenzanthrone (3-nitro-7H-benz [de]anthracen-7-one, 3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and air pollution. We compared the ability of human hepatic cytosolic samples to catalyze DNA adduct formation by 3-NBA. Using the 32 P-postlabeling method, we found that 12/12 hepatic cytosols activated 3-NBA to form multiple DNA adducts similar to those formed in vivo in rodents. By comparing 3-NBA-DNA adduct formation in the presence of cofactors of NAD(P)H:quinone oxidoreductase (NQO1) and xanthine oxidase, most of the reductive activation of 3-NBA in human hepatic cytosols was attributed to NQO1. Inhibition of adduct formation by dicoumarol, an NQO1 inhibitor, supported this finding and was confirmed with human recombinant NQO1. When cofactors of N,Oacetyltransferases (NAT) and sulfotransferases (SULT) were added to cytosolic samples, 3-NBA-DNA adduct formation increased 10-to 35-fold. Using human recombinant NQO1 and NATs or SULTs, we found that mainly NAT2, followed by SULT1A2, NAT1, and, to a lesser extent, SULT1A1 activate 3-NBA. We also evaluated the role of hepatic NADPH:cytochrome P450 oxidoreductase (POR) in the activation of 3-NBA in vivo by treating hepatic POR-null mice and wild-type littermates i.p. with 0.2 or 2 mg/kg body weight of 3-NBA. No difference in DNA binding was found in any tissue examined (liver, lung, kidney, bladder, and colon) between null and wild-type mice, indicating that 3-NBA is predominantly activated by cytosolic nitroreductases rather than microsomal POR. Collectively, these results show the role of human hepatic NQO1 to reduce 3-NBA to species being further activated by NATs and SULTs. (Cancer Res 2005; 65(7): 2644-52)

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Section: Introductionmentioning

confidence: 99%

“…3-NBA induces micronuclei (MN) in human B-lymphoblastoid MCL-5 and h1A1v2 cells [Arlt et al, 2004a;Phousongphouang et al, 2000], HepG2 cells [Lamy et al, 2004], and mouse peripheral blood reticulocytes [Enya et al, 1997;Arlt et al, 2004c]. 3-NBA causes DNA damage in human MCL-5 [Arlt et al, 2004a] and HepG2 cells [Lamy et al, 2004], and induces gene mutations at the TK and HPRT loci in MCL-5 and h1A1v2 cells [Phousongphouang et al, 2000]. 3-NBA-derived DNA adducts have been detected in vitro in calf thymus DNA [Enya et al, 1998;Bieler et al, 1999], Chinese hamster V79 cells [Arlt et al, 2003a], human HepG2 [Kawanishi et al, 2000], and human lymphoblastoid MCL-5 cells [Arlt et al, 2004a].…”

Section: Introductionmentioning

confidence: 99%

Tissue‐specific metabolic activation and mutagenicity of 3‐nitrobenzanthrone in Muta™Mouse

Chen

Soper

Douglas

et al. 2008

Environ and Mol Mutagen

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3-Nitrobenzanthrone (3-NBA) is a mutagen and suspected human carcinogen detected in diesel exhaust, airborne particulate matter, and urban soil. We investigated the tissue specific mutagenicity of 3-NBA at the lacZ locus of transgenic MutaMouse following acute single dose or 28-day repeated-dose oral administration. In the acute high dose (50 mg/kg) exposure, increased lacZ mutant frequency was observed in bone marrow and colonic epithelium, but not in liver and bladder. In the repeated-dose study, a dose-dependent increase in lacZ mutant frequency was observed in bone marrow and liver (2- and 4-fold increase above control), but not in lung or intestinal epithelium. In addition, a concentration-dependent increase in mutant frequency (8.5-fold above control) was observed for MutaMouse FE1 lung epithelial cells exposed in vitro. 1-Nitropyrene reductase, 3-NBA reductase, and acetyltransferase activities were measured in a variety of MutaMouse specimens in an effort to link metabolic activation and mutagenicity. High 3-NBA nitroreductase activities were observed in lung, liver, colon and bladder, and detectable N-acetyltransferase activities were found in all tissues except bone marrow. The relatively high 3-NBA nitroreductase activity in MutaMouse tissues, as compared with those in Salmonella TA98 and TA100, suggests that 3-NBA is readily reduced and activated in vivo. High 3-NBA nitroreductase levels in liver and colon are consistent with the elevated lacZ mutant frequency values, and previously noted inductions of hepatic DNA adducts. Despite an absence of induced lacZ mutations, the highest 3-NBA reductase activity was detected in lung. Further studies are warranted, especially following inhalation or intratracheal exposures.

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3-Nitrobenzanthrone (3-NBA) induced micronucleus formation and DNA damage in human hepatoma (HepG2) cells

Cited by 60 publications

References 28 publications

Genotoxicity of nitrosulfonic acids, nitrobenzoic acids, and nitrobenzylalcohols, pollutants commonly found in ground water near ammunition facilities

Genotoxicity of nitrosulfonic acids, nitrobenzoic acids, and nitrobenzylalcohols, pollutants commonly found in ground water near ammunition facilities

Environmental Pollutant and Potent Mutagen 3-Nitrobenzanthrone Forms DNA Adducts after Reduction by NAD(P)H:Quinone Oxidoreductase and Conjugation by Acetyltransferases and Sulfotransferases in Human Hepatic Cytosols

Tissue‐specific metabolic activation and mutagenicity of 3‐nitrobenzanthrone in Muta™Mouse

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