Document Detail


Genotoxicity of 2,6- and 3,5-dimethylaniline in cultured mammalian cells: the role of reactive oxygen species.
MedLine Citation:
PMID:  22831970     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Several alkylanilines with structures more complex than toluidines have been associated epidemiologically with human cancer. Their mechanism of action remains largely undetermined, and there is no reported evidence that it replicates that of multicyclic aromatic amines even though the principal metabolic pathways of P450-mediated hydroxylation and phase II conjugation are very similar. As a means to elucidate their mechanisms of action, lethality and mutagenicity in the adenine phosphoribosyltransferase (aprt (+/-)) gene induced in several Chinese hamster ovary cell types by 2,6- and 3,5-dimethylaniline (2,6-DMA, 3,5-DMA) and their N- and ring-hydroxyl derivatives (N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, 3,5-DMAP) were assessed. Dose-response relationships were determined in the parental AA8 cell line, its repair-deficient UV5 subclone and other repair-deficient 5P3NAT2 or -proficient 5P3NAT2R9 subclones engineered to express mouse cytochrome P4501A2 (CYP1A2) and human N-acetyltransferase (NAT2), and also in AS52 cells harboring the bacterial guanine-hypoxanthine phosphoribosyltransferase (gpt) gene. Mutations in the gpt gene of AS52 cells were characterized and found to be dominated by G:C to A:T and A:T to G:C transitions. Separately, treatment of AS52 cells with N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, 3,5-DMAP, and 3,5-DMAP led to intracellular production of reactive oxygen species (ROS) for at least 24h after removal of the mutagens in every case. Using the comet assay, DNA strand breaks were observed in a dose-dependent manner in AS52 cells when treated with each of the four N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, and 3,5-DMAP derivatives. Comparative evaluation of the results indicates that the principal mechanism of mutagenic action is likely to be through redox cycling of intracellularly bound aminophenol/quinone imine structures to generate ROS rather than through formation of covalent DNA adducts.
Authors:
Ming-Wei Chao; Min Young Kim; Wenjie Ye; Jing Ge; Laura J Trudel; Crystal L Belanger; Paul L Skipper; Bevin P Engelward; Steven R Tannenbaum; Gerald N Wogan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-24
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  130     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-19     Completed Date:  2013-03-27     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  48-59     Citation Subset:  IM    
Affiliation:
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Aniline Compounds / metabolism,  toxicity*
Animals
CHO Cells
Cell Survival / drug effects
Cells, Cultured
Cricetinae
Cricetulus
DNA Adducts
DNA Breaks, Double-Stranded / drug effects
Dose-Response Relationship, Drug
Humans
Mice
Microsomes, Liver / drug effects,  metabolism
Mutagenicity Tests
Mutagens / metabolism,  toxicity*
Mutation / drug effects
Oxidation-Reduction
Reactive Oxygen Species / metabolism*
Grant Support
ID/Acronym/Agency:
ES02109/ES/NIEHS NIH HHS; P01-ES006052/ES/NIEHS NIH HHS; U01-ES016045/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Aniline Compounds; 0/DNA Adducts; 0/Mutagens; 0/Reactive Oxygen Species; 1418BR6T2H/3,5-dimethylaniline; 4FT62OX08D/2,6-xylidine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Cadmium intake and systemic exposure in postmenopausal women and age-matched men who smoke cigarette...
Next Document:  Group-level impact of work environment dimensions on burnout experiences among nurses: A multivariat...