The purpose of this program is to elucidate certain biochemical processes that are involved in the toxicity of aromatic amines and nitroso aromatic compounds. As a group the aromatic amines comprise some of mankind's most important industrial chemicals. Their extensive use as pesticides in modern agricultural practice continues to increase, yet a knowledge of their biological fate and effects in living organisms is very incomplete. Since many aromatic amines and related chemicals are known carcinogens, it is necessary that a detailed knowledge of the metabolism of these chemicals in higher animals be attained. This program will study the extent to which model aromatic amines are metabolized to hydroxamic acids, since hydroxamic acids are known to account for much of the toxicity of aromatic amines. The program will examine the biochemical processes that convert nitroso aromatic compounds to hydroxamic acids possessing unusual N-acyl groups. The specific biochemical pathways responsible for such hydroxamic acids arise from the interaction of a nitroso aromatic compound with a thiamine-dependent enzyme. Another facile, but non-enzymatic reaction that causes the production of the N-formyl type hydroxamic acids is the reaction of a nitroso aromatic with glyoxylic acid. Primary hepatocyte cultures prepared from rats will be the principal system in which these studies will be conducted, although for comparative purposes primary hepatocyte cultures for syrian hamsters will also be used. The results of this program will provide valuable data to help design measures to minimize mankind's exposure to or damage from potentially genotoxic chemicals.
| Corbett, M D; Lim, L O; Corbett, B R et al. (1988) Covalent binding of N-hydroxy-N-acetyl-2-aminofluorene and N-hydroxy-N-glycolyl-2-aminofluorene to rat hepatocyte DNA: in vitro and cell-suspension studies. Chem Res Toxicol 1:41-6 |
| Corbett, M D; Wei, C; Corbett, B R (1985) Nitroreductase-dependent mutagenicity of p-nitrophenylhydroxylamine and its N-acetyl and N-formyl hydroxamic acids. Carcinogenesis 6:727-32 |
