In Vitro Rat Hepatic and Intestinal Metabolism of the Organophosphate Pesticides Chlorpyrifos and Diazinon

Details

• Personal Author:
  Kousba AA ; Poet TS ; Timchalk C ; Wu H
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Energy Metabolism Insecticides Laboratories Occupational Health Safety
• Keywords:
  Animal-studies Author Keywords: Chlorpyrifos Diazinon Hepatocytes In-vitro-studies In-vitro-study Intestine Laboratory-animals Liver Metabolism Organophosphate Insecticides

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 10 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  193-200
• Volume:
  72
• Issue:
  2
• NIOSHTIC Number:
  nn:20029229
• Citation:
  Toxicol Sci 2003 Apr; 72(2):193-200
• Contact Point Address:
  Battelle, Pacific Northwest Division, Chemical Dosimetry, P.O. Box 999, Richland, Washington 99352, USA
• Email:
  torka.poet@pnl.gov
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Diazinon (CAS RN 333-41-5)
• Federal Fiscal Year:
  2003
• NORA Priority Area:
  Research Tools and Approaches: Exposure Assessment Methods
• Performing Organization:
  Battelle Memorial Institute, Richland, Washington
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Toxicological Sciences
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:371b6b26cf92ce71fd9be30c0eed780413b15849f3f56c555143ac51518c9ef6e16fa8d4ea36a3f32ea2abbc49c570d110071ab5ca0080f614f0d92d79c5593a
• Download URL:
  https://stacks.cdc.gov/view/cdc/190262/cdc_190262_DS1.pdf
• File Type:
  [PDF - 133.62 KB ]