Aromatic amines are used as industrial intermediates in the rubber, dye and pharmaceutical industries. The major toxic responses to this class of chemicals are the production of methemoglobin and tumors. Aromatic amines are substrates of N-acetyltransferase, an enzyme that is under polymorphic genetic control. This trait has been linked to susceptibility to aromatic amine toxicity; slow acetylators are more likely to develop methemoglobin following exposure to aniline or urinary bladder cancer following exposure to 2-naphthylamine or benzidine. The proposed studies will focus on delineating the role of N-acetylation in the development of aromatic amine toxicity. The objectives are 1). to correlate acetylator phenotype with metabolite profiles of model aromatic amines; 2). to evaluate methemoglobin formation in rapid and slow acetylators; 3). to investigate the role of methemoglobin in the development of splenic pathology; and 4). to compare in vivo in both phenotypes. Aniline and benzidine will be utilized as the model aromatic amines. Studies will be done in mice, in parental and congenic strains expressing the acetylator polymorphism. Urinary and blood metabolite profiles will be obtained by HPLC analysis for both phenotypes. Animals will be exposed to aniline or benzidine and methemoglobin formation and splenic damage will be determined. DNA damage in erythrocytes, liver, kidney and spleen will be examined by adduct formation of DNA strand breaks.
