Hemoglobin Binding of Nitroarenes and Quantitative Structure-Activity Relationships

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Abstract
Nitroarenes are important intermediates in industrial manufacturing and are found as environmental pollutants. Reduction of the nitro group to yield nitro radical anions, nitrosoarenes, and N-hydroxyarylamines is a crucial metabolic step for the genotoxic and cytotoxic properties of nitroarenes. N-Hydroxyarylamines can form adducts with DNA, with tissue proteins, and with the blood proteins: albumin and hemoglobin. The determination of hemoglobin adducts is an established method for biomonitoring populations exposed to aromatic amines. We determined the hemoglobin binding index (HBI) [(mmol compound/mol Hb)/(mmol compound/kg body weight)] of several nitroarenes in female Wistar rats. The logarithm of hemoglobin binding (log HBI) was plotted against several physicochemical parameters and against calculated electronic descriptors of nitroarenes. Most nitroarenes form hydrolyzable (e.g. sulphinamide) adducts with hemoglobin in rats. The extent of hemoglobin binding of nitroarenes increases with the reducibility of the nitro group, except for a few outliers. The structure activity relationships (SARs) for hemoglobin binding of nitroarenes and arylamines are similar. The SARs found for hemoglobin binding were comparable to the SARs found in the literature for mutagenicity and cytotoxicity of nitroarenes. In general cytotoxicity in rat hepatocytes, hemoglobin binding in rats and mutagenicity in Salmonella typhimurium increase with reducibility of the nitro group. Insufficient data are available to establish a SAR for the carcinogenicity of nitroarenes.

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