Hemoglobin binding of arylamines and nitroarenes: molecular dosimetry and quantitative structure-activity relationships

Abstract

N-Oxidation and nitroreduction to yield N-hydroxyarylamines are metabolic steps that are crucial for the genotoxic properties of aromatic amines and nitroarenes, respectively. N-Hydroxyarylamines can form adducts with DNA, tissue proteins, and the blood proteins albumin and hemoglobin in a dose-dependent manner. The determination of hemoglobin adducts is a useful tool for biomonitoring exposed populations. We have established the hemoglobin binding index (HBI) [(mmole compound/mole Hb)/(mmole compound/kg body weight)] of several aromatic amines and nitroarenes in female Wistar rats. Incorporating values obtained by other researchers in the same rat strain, the logarithm of hemoglobin binding (log HBI) was plotted against several physicochemical parameters and against calculated electronic descriptors of nitroarenes and arylamines. Most arylamines and nitroarenes form hydrolyzable (e.g., sulfinamide) adducts with hemoglobin in rats. The amount of hemoglobin binding decreases with the oxidizability of the arylamines, except for compounds that are substituted with halogens in ortho or meta position. For halogen-substituted arylamines, the amount of hemoglobin binding is directly proportional to the pKa. Hemoglobin binding of nitroarenes increases with the reducibility of the nitro group. The structure activity relationships (SAR) for hemoglobin binding of nitroarenes and arylamines are comparable. The SAR found for hemoglobin binding were compared with the SAR found in the literature for mutagenicity, carcinogenicity, and cytotoxicity of arylamines and nitroarenes. 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.(ABSTRACT TRUNCATED AT 250 WORDS)