The purpose of this program is to elucidate certain biochemical processes that are partially responsible for the genotoxicity of arylamines and nitroso aromatic compounds. The arylamines constitute some of our most important chemicals. Arylamines and derivatives are common pharmaceutical agents and the extensive use of arylamine derivatives as pesticides in modern agricultural practice continues to increase. On the other hand, a knowledge of the biological fate and effects of arylamines in living organisms is very incomplete. Since many arylamines 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 thiamin-dependent enzyme. Another facile, but non-enzymatic reaction that causes the production of the N-formyl type hydroxamic acid under physiological conditions is the reaction a nitroso aromatic with glyoxylic acid. The bioactivation reactions of interest will be studied by employing leukocytes, since these blood cells comprise sizable and highly disseminated tissues. Total and purified leukocyte types (neutrophils, monocytes, macrophages, lymphocytes) will be obtained from New Zealand white rabbits, Syrian golden hamsters, Sprague Dawley rats and banked human blood. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003631-02
Application #
3251127
Study Section
Toxicology Study Section (TOX)
Project Start
1985-06-01
Project End
1988-05-31
Budget Start
1986-06-01
Budget End
1987-05-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Earth Sciences/Resources
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Corbett, M D; Corbett, B R; Hannothiaux, M H et al. (1992) The covalent binding of acetaminophen to cellular nucleic acids as the result of the respiratory burst of neutrophils derived from the HL-60 cell line. Toxicol Appl Pharmacol 113:80-6
Doerge, D R; Corbett, M D (1991) Peroxygenation mechanism for chloroperoxidase-catalyzed N-oxidation of arylamines. Chem Res Toxicol 4:556-60
Corbett, M D; Hannothiaux, M H; Corbett, B R et al. (1991) A comparison of the HL-60 cell line and human granulocytes to effect the bioactivation of arylamines and related xenobiotics. The binding of 2-aminofluorene to nucleic acids as the result of the respiratory burst. Chem Biol Interact 78:33-54
Corbett, M D; Corbett, B R; Quintana, S J et al. (1990) Microsomal N-hydroxylation of the glycolamide 2-(glycolylamino)fluorene to give the glycolylhydroxamic acid. A new xenobiotic reaction. Chem Res Toxicol 3:296-300
Corbett, M D; Corbett, B R; Hannothiaux, M H et al. (1989) Metabolic activation and nucleic acid binding of acetaminophen and related arylamine substrates by the respiratory burst of human granulocytes. Chem Res Toxicol 2:260-6
Corbett, M D; Corbett, B R (1988) N-glycolylhydroxamic acids: an improved synthetic method and the in situ generation and intramolecular rearrangement of N-acetoxy-N-glycolyl-2-aminofluorene. Chem Res Toxicol 1:222-7
Corbett, M D; Corbett, B R (1988) Nucleic acid binding of arylamines during the respiratory burst of human granulocytes. Chem Res Toxicol 1:356-63
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 I; Johnston, J J et al. (1987) Mutagenicity of the C-nitroso analog of fenitrothion. Toxicol Lett 35:201-7
Corbett, M D; Corbett, B R (1987) HRP-catalyzed bioactivation of carcinogenic hydroxamic acids. The greater reactivity of glycolyl- versus acetyl-derived hydroxamic acids. Chem Biol Interact 63:249-64