Received for publication March 15, 2006.
Revised July 10, 2006.
Accepted for publication July 11, 2006.

Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: Differential oxidative and hydrolytic metabolism by humans and rats

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 utilized 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 (CL_INT) of esfenvalerate was estimated to be three-fold greater in rodents than in humans on a per kg 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 CL_INT for deltamethrin was estimated to be two-fold more rapid in humans than in rats on a per kg body weight basis. Metabolism by purified rat and human carboxylesterases (CEs) were utilized 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 towards 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, while 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.

Key words: cytochrome P450 catalyzed oxidations, insecticides, liver microsomes, toxicokinetics

This article has been cited by other articles:

				E. J. Scollon, J. M. Starr, S. J. Godin, M. J. DeVito, and M. F. Hughes In Vitro Metabolism of Pyrethroid Pesticides by Rat and Human Hepatic Microsomes and Cytochrome P450 Isoforms Drug Metab. Dispos., January 1, 2009; 37(1): 221 - 228. [Abstract] [Full Text] [PDF]

				K.-B. Kim, S. S. Anand, H. J. Kim, C. A. White, and J. V. Bruckner Toxicokinetics and Tissue Distribution of Deltamethrin in Adult Sprague Dawley Rats Toxicol. Sci., February 1, 2008; 101(2): 197 - 205. [Abstract] [Full Text] [PDF]

				S. J. Godin, J. A. Crow, E. J. Scollon, M. F. Hughes, M. J. DeVito, and M. K. Ross Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate Drug Metab. Dispos., September 1, 2007; 35(9): 1664 - 1671. [Abstract] [Full Text] [PDF]