Mechanisms of toxicity and carcinogenicity of three alkylanilines

Alkyl-substituted anilines have been implicated as important etiological agents in human carcinogenesis. Specifically, 2,6-dimethylaniline (2,6-DMA), 3,5-dimethylaniline (3,5-DMA), and 3-ethylaniline (3EA) have been associated with an increased risk of human bladder cancer, independent of cigarette smoking, in a published case-control study. Understanding the metabolic activation of and DNA adduct formation by these chemicals is an important first step in elucidating their mechanisms of carcinogenesis and toxicity. Cytochrome P450-mediated metabolism was profiled based on the hypothesis that N-hydroxylated metabolites are critical intermediates in the formation of DNA adducts. This work was extended to assess in vitro DNA adduct formation with the cell-free and cell-based assays. Accelerator Mass Spectrometry (AMS) was used for detection and semi-quantification of DNA adducts formed by 14C-labeled alkylanilines. Data indicated 3,5-DMA formed high levels of DNA adducts, suggesting that it is a potent carcinogen. Additionally, the levels of adducts exhibited inter-species variation. The effects of phase II metabolism on adduct formation were evaluated by comparing the results obtained from the two types of assays and by assessing the effects of phase II enzyme cofactors on the results of cell-free assay.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2006

Author dc:creator

• Sun, Hsiao-Lan Patty

Advisor dc:contributor.advisor

• Steven R. Tannenbaum.

• Biological Engineering Division.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/37958

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/37958