Salmonella typhimurium mutagenicity tester strains that overexpress oxygen-insensitive nitroreductases nfsA and nfsB

Carroll, C.; Warnakulasuriyarachchi, D.; Nokhbeh, M.R.; Lambert, Iain B.

doi:10.1016/s0027-5107(02)00018-0

Cited by 40 publications

(33 citation statements)

References 78 publications

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“…This suggests that the Salmonella classical nitroreductase (i.e., Cnr) in YG1021 is not required for 3-NBA reduction, and thus, the major nitroreductase (i.e., SnrA) can effectively reduce 3-NBA. A similar pattern has also been observed for di-nitroPAHs such as 1, 8-dinitropyrene [Enya et al, 1997;Carroll et al, 2002]. The high directacting mutagenicity of 3-NBA, like that of the dinitropyrenes, is likely due to the high reduction potential (E 1/2 ) of the nitro group, and the relative ease for formation of the hydronitroxide radical or hydroxylarylamine [Ritter and Malejka-Giganti, 1998].…”

Section: Discussionsupporting

confidence: 61%

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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Section: Discussionsupporting

confidence: 61%

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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“…The NAT-dependence of the mutagenicity of nitro derivatives of heterocyclic amines such as IQ is well known [42, 43]. The nitro compounds are activated by nitroreductase-catalyzed reduction [44] to the corresponding hydroxylamines, which are then esterified to N-acetoxy esters by acetyltransferase. However, the NAT dependence of the mutagenicity of the N-nitroso derivatives was unexpected, since there is not an obvious role for acetylation in their activation (see Discussion).…”

Section: Resultsmentioning

confidence: 99%

Activation of aminoimidazole carcinogens by nitrosation: Mutagenicity and nucleotide adducts

Zenser

Lakshmi

Schut

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Abstract2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx) are heterocyclic amines (HCA) derived from high temperature cooking of meat and thought to cause colon cancer in humans. Reactive nitrogen oxygen species, which are mediators of the inflammatory response, can convert these amines to the corresponding N-nitrosamines, N-NO-IQ and N-NO-MeIQx. This study was designed to evaluate whether these N-nitrosamines are genotoxic and could be responsible, in part, for the high incidence of colon cancer in individuals with colitis. Such an association would counsel reduced intake of well-done red meat by colitis patients. Mutagenicity was evaluated by reversion of a lacZ frameshift allele in three different E. coli strains. Strains DJ701 and DJ702 express recombinant (S. typhimurium) aromatic amine N-acetyltransferase; DJ702 also expresses recombinant human cytochrome P450 1A2 and NADPH-P450 reductase; and DJ2002 served as an N-acetyltransferase-negative control. In strain DJ701, N-NO-IQ and N-NOMeIQx elicited dose-dependent mutagenicity, which was not further increased in DJ702. Neither nitrosamine was mutagenic in strain DJ2002. While both N-nitrosamines are stable for >4 hours (pH 7.4, 37°C), they react with DNA or 2′-deoxyguanosine 3′-monophosphate at lower pH (5.5) to form adducts. HOCl, a component of the inflammatory response, increased adduct formation, as measured by 32 P-postlabeling. Following treatment with nuclease P1 and separation by two-dimensional thinlayer chromatography and then HPLC, N-NO-IQ and N-NO-MeIQx were shown to form the same adducts as those formed by N-OH-MeIQx or N-OH-IQ, namely N-(deoxyguanosin-8-yl) adducts. In summary, these N-nitrosamines are genotoxic and might be alternatives to their hydroxylamine analogues as activated intermediates leading to initiation of colon cancer in individuals with colitis.

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“…The induction of À2 frameshifts by nitracrine and 3-nitro-DAPA (Table III) and by Entozon (Table V) can be ascribed to reactive intermediates that bind to DNA covalently, but the specific nitroreductases involved are uncertain. Entozon exhibits full mutagenic activity in TA98NR [McCoy et al, 1981], which lacks both the major (SnrA) and minor (Cnr) oxygen-insensitive nitroreductases [Carroll et al, 2002;Nokhbeh et al, 2002]. Results in Salmonella strains TA98NR and TA98 suggest that the classical nitroreductase (Cnr) is effective in activating nitracrine but less so in the case of 3-nitro-DAPA [Ferguson et al, 1987].…”

Section: Discussionmentioning

confidence: 99%

“…The major oxygen-insensitive nitroreductase is encoded by the nfsA gene in E. coli and by snrA in Salmonella enterica (serovar Typhimurium) [Carroll et al, 2002;Nokhbeh et al, 2002]. The SnrA enzyme is present in some Ames tester strains (e.g., TA1535), but it is lacking in strains TA1538 and TA98 [Yamada et al, 1997;Nokhbeh et al, 2002].…”

Section: Discussionmentioning

confidence: 99%

“…The SnrA enzyme is present in some Ames tester strains (e.g., TA1535), but it is lacking in strains TA1538 and TA98 [Yamada et al, 1997;Nokhbeh et al, 2002]. The flavin-dependent classical nitroreductase of Salmonella, which is present in TA1538 and TA98, is encoded by the cnr gene and is homologous with the E. coli minor oxygen-insensitive nitroreductase encoded by nfsB [Yamada et al, 1997;Carroll et al, 2002;Nokhbeh et al, 2002]. Decreased mutagenicity of nitro compounds in strains TA1538NR and TA98NR is ascribable to a lack of Cnr, the classical nitroreductase [Ferguson et al, 1987;Josephy et al, 1997;Watanabe et al, 1998].…”

Section: Discussionmentioning

confidence: 99%

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Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in thelacZ reversion assay inEscherichia coli

Hoffmann

Yin

Terry

et al. 2006

Environ. Mol. Mutagen.

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Acridines are well-known as compounds that intercalate noncovalently between DNA base pairs and induce +/-1 frameshift mutations at sites of monotonous repeats of a single base. Reactive derivatives of acridines, including acridine mustards and nitroacridines, form covalent adducts in DNA and exhibit mutagenic properties different from the simple intercalators. We compared the frameshift mutagenicity of the cancer chemotherapy drug nitracrine (1-nitro-9-(3'-dimethylaminopropylamino)-acridine), its des-nitro counterpart 9-(3'-dimethylaminopropylamino)-acridine (DAPA), and its 2-, 3-, and 4-nitro isomers (2-, 3-, and 4-nitro-DAPA) in the lacZ reversion assay in Escherichia coli. DAPA is a simple intercalator, much like the widely studied 9-aminoacridine. It most strongly induced +/-1 frameshift mutations in runs of guanine residues and more weakly induced -1 frameshifts in a run of adenine residues. A nitro group in the 1, 3, or 4 position of DAPA reduced the yield of +/-1 frameshift mutations. DAPA weakly induced -2 frameshifts in an alternating CG sequence. In contrast, nitracrine and its 3-nitro isomer resembled the 3-nitroacridine Entozon in effectively inducing -2 frameshift mutations. The 2- and 4-nitro isomers were less effective than the 1- and 3-nitro compounds in -2 frameshift mutagenesis. The results are interpreted with respect to intercalation, steric interactions, effects of base strength on DNA binding, enzymatic processing, and a slipped mispairing model of frameshift mutagenesis.

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Salmonella typhimurium mutagenicity tester strains that overexpress oxygen-insensitive nitroreductases nfsA and nfsB

Cited by 40 publications

References 78 publications

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

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

Activation of aminoimidazole carcinogens by nitrosation: Mutagenicity and nucleotide adducts

Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in thelacZ reversion assay inEscherichia coli

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