The overall objective of this proposal is to provide information which will aid in the identification of conditions in which individuals might be unusually susceptible (or resistant) to the toxic actions of pesticides. The project will focus on the organophosphorus insecticides since they represent the major class of chemicals used as insecticides, and since they have potential for serious toxic effects in humans. Research will be directed towards characterizing those factors which affect the mammalian biotransformation reactions of organophosphorus insecticides, as well as the consequences of such reactions. It is expected that these studies will provide information useful in assessing the health hazards of organophosphorus insecticides, as well as their potential for toxic interactions with certain other foreign chemicals. Additionally this proposed research will contribute to the fundamental knowledge of those metabolic systems involved in the biotransformation of these insecticides.
The specific aims i n this research are as follows: 1) To continue to investigate the toxicological significance of extrahepatic activation of certain organothiophosphorus insecticides. 2) To investigate why glutathione-dependent detoxification of numerous dimethyl-substituted organophosphorus insecticides occurs in vitro but not in vivo. 3) To identify and characterize factors which affect hepatic and serum A-esterase activities. Included in this aim will be the investigation of kinetic and physiochemical differences between """"""""high activity"""""""" and """"""""low activity"""""""" forms of human serum A-esterase. 4) To characterize biochemically the two forms of A-esterase purified from mouse hepatic microsomes in this laboratory. 5) To characterize the factors affecting secretion of A-esterase(s) from liver. These studies will also focus on comparisons of the secreted form(s) of A-esterase(s) with those forms found in hepatic microsomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004335-07
Application #
3252431
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1986-08-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Agyeman, A A; Sultatos, L G (1998) The actions of the H2-blocker cimetidine on the toxicity and biotransformation of the phosphorothioate insecticide parathion. Toxicology 128:207-18
Ramos, S; Sultatos, L (1998) Flavonoid-induced alterations in cytochrome P450-dependent biotransformation of the organophosphorus insecticide parathion in the mouse. Toxicology 131:155-67
Berger Jr, C W; Sultatos, L G (1997) The effects of the phosphorothioate insecticide fenitrothion on mammalian cytochrome P450-dependent metabolism of estradiol. Fundam Appl Toxicol 37:150-7
Vitarius, J A; O'Shaughnessy, J A; Sultatos, L G (1995) The effects of phenobarbital pretreatment on the metabolism and toxicity of paraoxon in the mouse. Pharmacol Toxicol 77:16-22
Vitarius, J A; Sultatos, L G (1995) The role of calcium in the hydrolysis of the organophosphate paraoxon by human serum A-esterase. Life Sci 56:125-34
O'Shaughnessy, J A; Sultatos, L G (1995) Interaction of ethanol and the organophosphorus insecticide parathion. Biochem Pharmacol 50:1925-32
Vitarius, J A; Sultatos, L G (1994) Kinetic mechanism of the detoxification of the organophosphate paraoxon by human serum A-esterase. Drug Metab Dispos 22:472-8
Huang, Y S; Woods, L; Sultatos, L G (1994) Solubilization and purification of A-esterase from mouse hepatic microsomes. Biochem Pharmacol 48:1273-80
Sultatos, L G (1994) Mammalian toxicology of organophosphorus pesticides. J Toxicol Environ Health 43:271-89
Huang, Y S; Sultatos, L G (1993) Glutathione-dependent biotransformation of methyl parathion by mouse liver in vitro. Toxicol Lett 68:275-84

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