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ToxSci Advance Access published online on March 7, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg035
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 26, 2002; accepted January 11, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

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

T. S. Poet 1*, H. Wu 1, A. A. Kousba 1, C. Timchalk 1

1 Battelle, Pacific Northwest Division, Chemical Dosimetry, PO Box 999, Richland, WA 99352, USA

* To whom correspondence should be addressed. E-mail: torka.poet{at}pnl.gov.


  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 form 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 PON1mediated 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 ~28-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was ~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. PON1mediated 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 enterocyte 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.

chlorpyrifos, diazinon, organophosphate insecticides, metabolism, liver, intestine .


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