Abstract
Pyrethroids are neurotoxic pesticides whose pharmacokinetic behavior plays a role in their potency. This study examined the elimination of esfenvalerate and deltamethrin from rat and human liver microsomes. A parent depletion approach in the presence and absence of NADPH was used to assess species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The intrinsic hepatic clearance (CLINT) of esfenvalerate was estimated to be 3-fold greater in rodents than in humans on a per kilogram body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes; however, in human liver microsomes, deltamethrin was eliminated almost entirely via NADPH-independent hydrolytic metabolism. The CLINT for deltamethrin was estimated to be 2-fold more rapid in humans than in rats on a per kilogram body weight basis. Metabolism by purified rat and human carboxylesterases (CEs) were used to further examine the species differences in hydrolysis of deltamethrin and esfenvalerate. Results of CE metabolism revealed that human carboxylesterase 1 (hCE-1) was markedly more active toward deltamethrin than the class 1 rat CEs hydrolase A and B and the class 2 human CE (hCE-2); however, hydrolase A metabolized esfenvalerate 2-fold faster than hCE-1, whereas hydrolase B and hCE-1 hydrolyzed esfenvalerate at equal rates. These studies demonstrate a significant species difference in the in vitro pathways of biotransformation of deltamethrin in rat and human liver microsomes, which is due in part to differences in the intrinsic activities of rat and human carboxylestersases.
Footnotes
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S.J.G. was supported by NHEERL-DESE, EPA CT826513. Research support was provided by National Institutes of Health Grants P20 RR017661 (to M.K.R.) and by National Institutes of Health Grants CA76202, CA79763, CA108775, CA98468, a Cancer Center Core Grant P30 CA-21765, and the American Lebanese Syrian Associated Charities (to P.M.P.).
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This article has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.010058.
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ABBREVIATIONS: TEPP, tetraethylpyrophosphate; CLINT, intrinsic hepatic clearance; hCE-1, human carboxylesterase 1; hCE-2, human carboxylesterase 2; MSP, microsomal protein; CE, carboxylesterase; P450, cytochrome P450.
- Received March 15, 2006.
- Accepted July 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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