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METABOLISM OF PYRETHROID PESTICIDES BY RAT AND HUMAN CYP450'S AND SERUM.
Citation:
GODIN, S., M. F. HUGHES, M. K. ROSS, AND M. J. DEVITO. METABOLISM OF PYRETHROID PESTICIDES BY RAT AND HUMAN CYP450'S AND SERUM. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
Pyrethroids are a class of neurotoxic pesticides in which the parent chemical acts via the modulation of nerve axon ion channels. Both the pharmacokinetic and pharmacodynamic behavior of pyrethroids play a role in their toxicity. The phase one biotransformation of pyrethroids can occur via cytochrome P450 mediated oxidation or esterase hydrolysis. Deltamethrin (delta) and esfenvalerate (esfen) are type II pyrethroid pesticides which are metabolized primarily by oxidative metabolism in rat liver microsomes. In human liver microsomes esfen is also metabolized primarily by oxidative metabolism. Delta in contrast is metabolized nearly entirely by hydrolysis in human liver microsomes. This research was aimed at determining which cytochrome P450 enzymes are responsible for the metabolism of delta and esfen in rat and human liver microsomes. In addition this research examined the metabolism of delta and esfen in rat and human serum. Initial studies indicate that rat CYP 1A1, 2C6, 2C11, and 3A2 metabolize both delta and esfen. Deltamethrin was metabolized most rapidly by 2C6 followed by 2C11>1A1> and 3A2. Esfenvalerate was metabolized most rapidly by 3A2 followed by 2C6>2C11> and 1A1. Esfenvalerate was also metabolized by human CYP2C9 while deltamethrin was not found to be metabolized significantly by any human P450¿s. The hydrolysis of pyrethroids has been shown to occur primarily via carboxylesterase. Rat serum which contains carboxylesterases metabolized both delta (15.33 ± 3.24 pmoles/min/mL) and esfen (9.97 ± 2.94 pmoles/min/mL). Human serum however which does not contain carboxylesterase did not metabolize either delta or esfen. These species differences in the liver and serum metabolism of delta and esfen may impact exposure-dose relationships between species for these pyrethroids. (SJG was supported in part by NHEERL-DESE, EPA CT826513. This abstract does not represent EPA policy)