Comparison of Hemoglobin Binding, Mutagenicity, and Carcinogenicity of Arylamines and Nitroarenes

Abstract

N-Oxidation and nitro-reduction which yield N-hydroxyarylamines are metabolic steps that are crucial for the genotoxic and toxic properties of aromatic amines and nitroarenes, respectively. N-Hydroxyarylamines form adducts with DNA, tissue proteins, and blood proteins. Except for nine compounds, it has been shown that after treatment of rats with nitroarenes (n = 31) or arylamines (n = 36) hydrolyzable hemoglobin adducts are formed as a result of the formation of the potentially genotoxic intermediate, N-hydroxyarylamine. Therefore, hemoglobin adducts are a good dosimeter of human exposure to a large array of arylamines and nitroarenes. The amount of hemoglobin binding decreases with the oxidizability of the arylamines, except for compounds which are substituted with halogens in the ortho- and/or meta-position. For halogen-substituted arylamines, the amount of hemoglobin binding is directly proportional to the pK_a. The level of hemoglobin binding and mutagenicity is directly proportional to the reducibility of the nitroarenes, but hemoglobin binding and mutagenicity do not correlate. In general the mutagenicity or carcinogenicity of arylamines increases with their oxidizability. This first set of data suggests that the levels of hemoglobin binding, mutagenicity, and carcinogenicity of arylamines are not determined by the same electronic properties of the compounds, or not by these properties alone. These results indicate that hemoglobin binding may prove not to be a useful index of the genotoxic potency of arylamines and nitroarenes. Further work is needed to investigate the relationship between hemoglobin binding and cytotoxicity of these compounds. However, the prospect that other blood proteins might be more suitable as biomarkers for biological effects of nitroarenes and arylamines needs to be investigated.