Carcinogenesis Advance Access first published online on November 3, 2009
This version published online on November 3, 2009
Carcinogenesis, doi:10.1093/carcin/bgp267
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Monocyclic Aromatic Amines as Potential Human Carcinogens: Old is New Again
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
* To whom correspondence should be addressed. Tel: 1-617-253-6792; Fax: 1-617-252-1787, Email: srt{at}mit.edu
Alkylanilines are a group of chemicals whose ubiquitous presence in the environment is a result of the multitude of sources from which they originate. Exposure assessments indicate that most individuals experience lifelong exposure to these compounds. Many alkylanilines have biological activity similar to that of the carcinogenic multi-ring aromatic amines. This review provides an overview of human exposure and biological effects. It also describes recent investigations into the biochemical mechanisms of action that lead to the assessment that they are most likely more complex than those of the more extensively investigated multi-ring aromatic amines. Not only is nitrenium ion chemistry implicated in DNA damage by alkylanilines, but also reactions involving quinone imines and perhaps reactive oxygen species. Recent results described here indicate that alkylanilines can be potent genotoxins for cultured mammalian cells when activated by exogenous or endogenous phase I and phase II xenobiotic metabolizing enzymes. The nature of specific DNA damage products responsible for mutagenicity remains to be identified but evidence to date supports mechanisms of activation through obligatory N-hydroxylation as well as subsequent conjugation by sulfation and/or acetylation. A fuller understanding of the mechanisms of alkylaniline genotoxicity is expected to provide important insights into the environmental and genetic origins of one or more human cancers and may reveal a substantial role for this group of compounds as potential human chemical carcinogens.
Key Words: aromatic amines • alkylanilines • mutagenicity • toxicity • dimethylanilines
Received September 22, 2009; revised October 24, 2009; accepted October 26, 2009.