Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

Ye, Wenjie; Seneviratne, Uthpala; Chao, Ming-Wei; Ravindra, Kodihalli C.; Wogan, Gerald N.; Tannenbaum, Steven R.; Skipper, Paul L.

doi:10.1021/tx3004517

Cited by 13 publications

(28 citation statements)

References 15 publications

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“…Ye et al . () has also suggested that 3,5‐DMAP can redox the cycle through the corresponding quinone imines to generate ROS. The electrophilic quinoneimine intermediate, 3,5‐DMQI, can react with protein thiols as a mechanism of immobilization in vivo .…”

Section: Discussionmentioning

confidence: 99%

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Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5‐dimethylaminophenol in AA8 cells

Chao

Erkekoğlu

Tseng

et al. 2014

J of Applied Toxicology

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Exposure to monocyclic aromatic alkylanilines (MAAs), namely 2,6-dimethylaniline (2,6-DMA), 3,5-dimethylaniline (3,5-DMA) and 3-ethylaniline (3-EA), was significantly and independently associated with bladder cancer incidence. 3,5-DMAP (3,5-dimethylaminophenol), a metabolite of 3,5-DMA, was shown to induce an imbalance in cytotoxicity cellular antioxidant/oxidant status, and DNA damage in mammalian cell lines. This study was designed to evaluate the protective effect of ascorbic acid (Asc) against the cytotoxicity, reactive oxygen species (ROS) production, genotoxicity and epigenetic changes induced by 3,5-DMAP in AA8 Chinese Hamster Ovary (CHO) cells. In different cellular fractions, 3,5-DMAP caused alterations in the enzyme activities orchestrating a cellular antioxidant balance, decreases in reduced glutathione levels and a cellular redox ratio as well as increases in lipid peroxidation and protein oxidation. We also suggest that the cellular stress caused by this particular alkylaniline leads to both genetic (Aprt mutagenesis) and epigenetic changes in histones 3 and 4 (H3 and H4). This may further cause molecular events triggering different pathological conditions and eventually cancer. In both cytoplasm and nucleus, Asc provided increases in 3,5-DMAP-reduced glutathione levels and cellular redox ratio and decreases in the lipid peroxidation and protein oxidation. Asc was also found to be protective against the genotoxic and epigenetic effects initiated by 3,5-DMAP. In addition, Asc supplied protection against the cell cycle (G1 phase) arrest induced by this particular alkylaniline metabolite.

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Section: Discussionmentioning

confidence: 99%

“…Previously, Ye et al . () has shown that 3,5‐DMAP anchored onto histone lysines (Lys) (Crott & Fenech, ; Ye et al ., ). Therefore, it is reasonable to assess whether Lys bound 3,5‐DMAP induces ROS generation in a cell‐free condition.…”

Section: Methodsmentioning

confidence: 99%

Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5‐dimethylaminophenol in AA8 cells

Chao

Erkekoğlu

Tseng

et al. 2014

J of Applied Toxicology

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“…Comparison of the two spectra confirms the tentative structure assignments for the fragments made previously. 5 In each case, scission of the lysine moiety’s epsilon carbon-nitrogen bond with loss of the DMAP moiety as a neutral gives the fragment ions at 130 (267 - 137) and 137 (275 – 138) amu from the analyte and IS, respectively. Here, the neutrals differ by one amu because the DMAP moiety of the IS includes an 15 N atom contributed by lysine through transimination.…”

Section: Resultsmentioning

confidence: 99%

“…Previous experiments 5 were limited to detecting monomeric DMHPL so contamination with other nuclear proteins could not be ruled out. In the present work, we isolated DMHPL-containing peptides with sequences specific to those found in the longer histone polypeptides.…”

Section: Resultsmentioning

confidence: 99%

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Hydroxyphenylation of Histone Lysines: Post-translational Modification by Quinone Imines

et al. 2016

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Monocyclic aromatic amines are widespread environmental contaminants with multiple sources such as combustion products, pharmaceuticals, and pesticides. Their phenolic metabolites are converted intracellularly to electrophilic quinone imines upon autoxidation and can embed in the cellular matrix through a transimination reaction that leaves a redox-active residue as a substituent of lysine side-chain amino groups. To demonstrate the occurrence of this process within the cellular nucleus, Chinese hamster ovary AA8 cells were treated with the para-phenol of 3,5-dimethylamine, after which the histone proteins were isolated, derivatized, and subjected to tryptic digestion. The resulting peptides were analyzed by tandem mass spectrometry to determine which lysines were modified. Nine residues in histones H2A, H2B, and H4 were identified; these were located in histone tails, close to where DNA makes contact with the nuclear core particle, elsewhere on the protein surface, and deep within the core. Kinetics of disappearance of the modified lysines in cultured cells was determined using isotope-dilution mass spectrometry. AA8 cells were also transfected with the genetically encoded hydrogen peroxide biosensor HyPer in constructs that lead to expression of HyPer in different cellular compartments. Challenging the resulting cells with the dimethylaminophenol resulted in sustained fluorescence emission in each of the compartments, demonstrating ongoing production of H2O2. The kinetics of modified lysine loss determined by mass spectrometry was consistent with persistence of HyPer fluorescence emission. We conclude that the para-phenol of 3,5-dimethylamine can become stably integrated into the histone proteins, which are minimally repaired if at all, and function as a persistent source of intracellular H2O2.

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Development and Validation of RP-UPLC Method for 2,6-Dimethylaniline, Its Isomers, and Related Compounds Using Design of Experiments

Marisetti¹,

Katari

2021

Chromatographia

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Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

Cited by 13 publications

References 15 publications

Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5‐dimethylaminophenol in AA8 cells

Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5‐dimethylaminophenol in AA8 cells

Hydroxyphenylation of Histone Lysines: Post-translational Modification by Quinone Imines

Development and Validation of RP-UPLC Method for 2,6-Dimethylaniline, Its Isomers, and Related Compounds Using Design of Experiments

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