monocyclic Aromatic Amines as Potential Human Carcinogens Old Is New Again

Review

doi: 10.1093/carcin/bgp267. Epub 2009 Nov 3.

Monocyclic aromatic amines as potential human carcinogens: old is new again

Affiliations

• PMID: 19887514
• PMCID: PMC2802674
• DOI: 10.1093/carcin/bgp267

Free PMC article

Review

Monocyclic aromatic amines as potential human carcinogens: old is new again

Paul L Skipper  et al. Carcinogenesis. 2010 Jan .

Free PMC article

Abstract

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 probably 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.

Figures

Fig. 1.

Environmental sources of alkylanilines.

Fig. 2.

Structures of the various alkylaniline DNA adducts that have been elucidated.

Fig. 3.

Formation of DNA adducts catalyzed by human S9 at low doses. Experimental details given in footnote to Table I except that the alkylaniline concentrations used were 25, 100 and 1000 nM.

Fig. 4.

Effect of Phase II conjugation activity on DNA adduct formation in vitro. NAT: All incubations were conducted in 0.2 ml 50 mM Tris buffer (pH 7.4) containing 1 mg/ml ct-DNA, 2 mg/ml human liver S9 fraction, NADPH-regenerating system and 1 μM of the respective [¹⁴C]amine for 6 h at 37°C. Supplementation was as follows: NAT, 1 mM ethylenediaminetetraacetic acid, 1 mM dithiothreitol, 1.08 mg/ml acetyl-

D

,

L

-carnitine, 0.22 U/ml carnitine acetyltransferase and 0.1 mM acetyl coenzyme A; SULF, 0.1 mM PAPS and UGT, 8 mM MgCl₂, 25 μg/ml alamethicin and 2 mM UDPGA.

Fig. 5.

Generation of aminophenols/quinone imines from N-hydroxylamines. The transformations shown here are alternative routes to aminophenols produced by direct ring oxidation by P450s.

Fig. 6.

Formation of protein adducts by aminophenols. A fundamental question posed by this article is whether similar reactions occur between aminophenols and DNA.

Fig. 7.

Proposed metabolic pathways leading to formation of genotoxic DNA damage products of 2,6-DMA. Modified from Gan et al. (24).

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Source: https://pubmed.ncbi.nlm.nih.gov/19887514/

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