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Intestinal metabolism of organophosphate insecticides: potential first-pass metabolism.

Wu H; Timchalk C; Kousba A; Poet TS
Toxicologist 2003 Mar; 72(S-1):91
Chlorpyrifos (CPF) and diazinon (DZN) are organophosphate (OP) insecticides, and their toxicity is mediated through CYP450 metabolism to CPF-oxon and DZN-oxon, respectively. Detoxification of CPF and DZN is also mediated by CYP450 and A-esterase (A-EST) metabolism of CPF- and DZN-oxon, resulting in the formation of trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. This study evaluated the potential role that intestinal metabolism (CYP450 and A-EST) may play in the first-pass clearance of OPs. Microsomes prepared from whole liver or isolated intestinal enterocytes demonstrated similar CYP450 and A-EST metabolic profiles. CYP450 content, as measured by reduced CO spectra, was approximately 10-fold lower in enterocyte than hepatocyte microsomes. For enterocyte CYP450 metabolism, the overall metabolic efficiency for the conversion to their active oxon metabolites was approximately 5-fold greater for CPF than DZN. When metabolism was compared per nmol P450 (nmol/min/nmol P450), the Vmax was approximately 3 and approximately 2 times higher in enterocytes than liver microsomes for CPF-oxon and TCP, respectively. The affinity (Km) for the metabolism of CPF to CPF-oxon was the same in liver and enterocyte microsomes, however the Km for TCP production was lower in enterocytes. Due to the smaller volume of intestine, the lower amount of CYP450, and the higher Km for TCP in the enterocyte microsomes, the catalytic efficiency was lower in intestine than liver for CPF-oxon, DZN-oxon and TCP. Enterocytes also demonstrated A-EST metabolism of CPF and DZN-oxon. Although the Km for the substrates were comparable in hepatic and enterocyte microsomes, the Vmax was significantly faster, 69- to 255-fold in liver. These results suggest that intestinal metabolism may impact first-pass metabolism of OPs following low-dose oral exposures that would be expected from residues on foods. (Sponsored by CDC/NIOSH Grant R01 OH03629-01A2 and EPA grant R828608).
Pesticides; Pesticides-and-agricultural-chemicals; Organo-phosphorus-pesticides; Organo-phosphorus-compounds; Insecticides; Metabolic-study
2921-88-2; 333-41-5
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Research Tools and Approaches: Exposure Assessment Methods
Source Name
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah
Performing Organization
Battelle Memorial Institute, Richland, Washington
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division