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1.
Scheme 2.

Scheme 2. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Derivation of the various cell lines related to the AA8 line. Adapted from Wu et al. (2003). RD, repair deficient; RP, repair proficient.

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
2.
FIG. 2.

FIG. 2. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Survival and mutagenicity of AA8 and UV5 cells treated with 3,5-DMAP. No difference in survival is apparent when cells were grown without ascorbate nor in the presence of ascorbate or NAC. In the absence of ascorbate, both cell lines become vulnerable to mutagenicity, which is largely abrogated in the presence of ascorbate or NAC. Vehicle control mutant frequency (typically, 2.9×10–5) subtracted before plotting.

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
3.
FIG. 4.

FIG. 4. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Intracellular production of ROS by 3,5-DMAP in AA8 and UV5 cells. ROS were detected as increased fluorescence after addition of a reduced dichlorofluorescein indicator dye. Cells were treated with test compounds for 1h, washed to remove residual free mutagen, and either assayed immediately (0h) or grown for 24h in fresh medium before assay (24h).

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
4.
FIG. 3.

FIG. 3. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Survival and mutagenicity of NAT2 cells treated with 3,5-DMAP, N-OH-3,5-DMA, and 3,5-DMA. This cell line expresses P450 1A2 and could thus treated with 3,5-DMA without exogenous S9 for the extended period of 48h. These cells also express N-acetyltransferase so the absence of a strong mutagenic response to N-OH-3,5-DMA suggests that the classic aromatic amine mechanism of DNA adduct formation is unimportant for this monocyclic amine. Vehicle control mutant frequency (typically, NAT2, 3.3×10−5; NAT2R9, 4.4×10−5) subtracted before plotting.

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
5.
FIG. 1.

FIG. 1. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Survival and mutagenicity of AS52 cells treated with 3,5-DMAP, N-OH-3,5-DMA, and 3,5-DMA + S9. Protection against cell killing by ascorbate and NAC is readily apparent when cells were treated with aminophenol (upper left panel) or N-hydroxylamine (lower left) but much less so when the amine was activated by exogenous S9 (lower right). Protection against mutagenicity (upper right) is less pronounced and even reversed with amine plus S9 treatment. Observed mutant frequencies were corrected by subtraction of the vehicle control value (typically, 1.7×10−5) before plotting.

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
6.
FIG. 5.

FIG. 5. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Intracellular production of ROS by hydroxylated dimethylanilines and inhibition by NAC. AS52 cells were treated with test compounds for 1h, washed to remove residual free mutagen, and grown in complete Ham’s medium for an additional 24h in the absence (solid symbols) or presence (open symbols) of 5mM NAC. Treatment with 2,6- and 3,5-DMA + S9 did not generate a significant response and are not shown. All dose-responses in the absence of NAC were statistically significant by linear regression analysis (p < 0.02). In the presence of NAC, only N-OH-3,5-DMA produced a significant dose-response (p < 0.01).

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
7.
FIG. 6.

FIG. 6. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Formation of DNA strand breaks by hydroxylated dimethylanilines. Strand breaks were detected using a microarray version of the comet assay (Wood et al., 2010). Each point represents the average of three independent experiments and each experiment includes 50 to 150 determinations. Cells treated with 50µM 3,5-DMAP demonstrated low viability, and only 20–50 comets were collected and analyzed from each experiment; however, a total of more than 100 determinations were obtained from three replicates. Standard error is plotted as error bars on the graph. Results noted with * differ from the negative control and from the same treatment in the presence of NAC by Student’s t-test with p < 0.05.

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.
8.
Scheme 1.

Scheme 1. From: Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species.

Three pathways to mutagenesis by dimethylanilines. These are shown for the 3,5-isomer and pertain equally to the 2,6-isomer. Arrows marked with * indicate reactions that are known to be or are potentially subject to catalysis. 1. The N-hydroxylamine undergoes N–O bond heterolysis, catalyzed by acyl- or sulfo-transferase activity that forms an unstable N-O- ester. The intermediate highly reactive nitrenium ion thus formed reacts with a DNA base to produce a mutagenic adduct. 2. The aminophenol produced by P450-catalyzed hydroxylation of the aniline or by nucleophilic attack of H2O on the appropriate resonance form of the nitrenium ion is oxidized to its quinone imine form. The electrophilic quinone imine undergoes nucleophilic addition by a DNA base yielding a mutagenic adduct. Chemical studies (Adams and Schowalter, 1952; Irving and Gutmann, 1961) have demonstrated that N-acylated or sulfonylated quinone imines readily undergo 1,2- and 1,4-substitution reactions with amine nucleophiles. 3. Quinone imines either directly or in protein-bound form undergo redox cycling to generate reactive oxygen species that oxidize guanine residues.

Ming-Wei Chao, et al. Toxicol Sci. 2012 November;130(1):48-59.

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