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An age-dependent physiologically based pharmacokinetic/pharmacodynamic model for the organophosphorus insecticide chlorpyrifos in the preweanling rat.

Authors
Timchalk-C; Kousba-AA; Poet-TS
Source
Toxicol Sci 2003 Apr; 72(2):193-200
NIOSHTIC No.
20032613
Abstract
Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate (OP) insecticides; their toxicity is mediated through CYP metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYPs also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase (PON1) metabolism of CPF- and DZN-oxon also forms TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in both the activation and detoxification of CPF and DZN in Sprague-Dawley rats. Similar CYP- and PON1-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. The metabolic efficiency was estimated by calculating the psuedo-1st order rate constant from the metabolic constants by dividing Vmax/Km. In enterocyte microsomes, the CYP metabolic efficiency for metabolism to the oxon metabolites was approximately 28-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was approximately 2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The Michaelis-Menten rate constant (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes; however, the enterocyte Km for TCP production was higher (indicating a lower affinity). The smaller volume of intestine, lower amount of CYP, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. PON1-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although PON1 affinity for the substrates was comparable in hepatic and enterocytic microsomes, the Vmax were 48- to 275-fold higher, in the liver. These results suggest that intestinal metabolism may impact the metabolism of CPF and DZN, especially following low-dose oral exposures.
Keywords
Insecticides; Laboratory-animals; Animal-studies; Hepatocytes; Metabolism; Intestinal-cells; Intestinal-tissue; Stomach-disorders; Detoxifying-agents; Detoxification
Contact
Charles Timchalk, Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352
CODEN
TOSCF2
CAS No.
2921-88-2; 333-41-5
Publication Date
20030401
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2003
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
Issue of Publication
2
ISSN
1096-6080
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Toxicological Sciences
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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