The objective of this research program is to elucidate the processes by which leukocytes cause the bioactivation or toxification of arylamines and related chemicals. Research will emphasize the ability of the various types of leukocytes to cause arylamines and aromatic hydroxamic acids to bind covalently with cellular macromolecules, a process which can lead to the disruption of normal cell function and cause cell death. The macromolecules of greatest interest are DNA and RNA. Covalent binding to these nucleic acids will be studied both within the leukocytes which are responsible for causing such binding, and also to nucleic acids outside the activating cells. The covalent binding of arylamines and hydroxamic acids to the macromolecules of cells that are not involved in the metabolic activation of such chemicals would indicate an important mechanism by which leukocytes can damage neighboring cells. The potential for phagocytic leukocytes (granulocytes, monocytes and macrophages) to cause damage to surrounding cells is already known to result from the release of reactive oxygen species following the normal """"""""respiratory burst"""""""" of such cells. The presence of xenobiotics, which are themselves susceptible to oxidation by these leukocyte products, could readily alter the nature of damage caused by these phagocytic cells. The reactive metabolites produced by leukocyte oxidation of arylamines and hydroxamic acids are known to bind to nucleic acids; therefore, the potential for genotoxic effects is of major concern. The emphasis on arylamines is because of the importance of this class of chemicals as a source for pharmaceuticals, pesticides and other environmental chemicals. The interest in hydroxamic acids arises from the fact that they are known to be arylamine metabolites that are produced primarily in the liver, and which are responsible in part for the genotoxic and necrotic properties of arylamines. Hydroxiamic acids are thought to be latentiated forms of metabolic activation products that can be transported to tissues throughout the body after being produced in the liver. Further transformation of hydroxamic acids is necessary for their potential toxicity to be released. Certain leukocytes are able to cause the final bioactivation of hydroxamic acids by mechanisms that will be studied in this program. A knowledge of the processes by which leukocytes cause the toxification of arylamines and hydroxamic acids will enable scientists to devise measures to minimize or prevent the adverse effects of such toxification reactions on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003631-07
Application #
3251131
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1985-06-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1993-06-30
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Earth Sciences/Natur
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