Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Abstract

ABSTRACT:The metabolism of (␣S)-cyano-3-phenoxybenzyl (1R, 3R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (deltamethrin) and (␣S)-cyano-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutyrate (esfenvalerate) by rat and human liver microsomes differs with respect to the biotransformation pathway (oxidation versus hydrolysis) responsible for their clearance. This study aims to further explore the species differences in the metabolism of these chemicals. Using a parent depletion approach, rat and human cytochromes P450 (P450s) were screened for their ability to eliminate deltamethrin or esfenvalerate during in vitro incubations. Rat P450 isoforms CYP1A1, CYP2C6, CYP2C11, and CYP3A2 and human P450 isoforms CYP2C8, CYP2C19, and CYP3A5 were capable of metabolizing either pyrethroid. Human CYP2C9 metabolized esfenvalerate but not deltamethrin. Rat and human P450s that metabolize esfenvalerate and deltamethrin do so with similar kinetics. In addition to the liver, a potential site of metabolic elimination of pyrethroids is the blood via serum carboxylesterase (CE) hydrolysis. The serum of rats, but not humans, contains significant quantities of CE. Deltamethrin and esfenvalerate were metabolized effectively by rat serum and a purified rat serum CE. In contrast, neither pyrethroid was metabolized by human serum or purified human serum esterases (acetylcholinesterase and butyrylcholinesterase). These studies suggest that the difference in rates of oxidative metabolism of pyrethroids by rat and human hepatic microsomes is dependent on the expression levels of individual P450 isoforms rather than their specific activity. Furthermore, these studies show that the metabolic elimination of deltamethrin and esfenvalerate in blood may be important to their disposition in rats but not in humans.

Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats

“…*P < 0.05 vs. control group. sure at the target tissue and increased potency (Godin et al, 2007). In addition, pyrethroids are highly lipophilic and by easily crossing the blood-brain-barrier they can reach the CNS at concentrations that can be potentially neurotoxic.…”

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

“…CYP-mediated oxidative metabolism of OPs and PYRs is complex and involves several pathways, as different CYP isoforms can metabolize the same compound (e.g., chlorpyrifos) and different compounds (e.g., deltamethrin) to different degrees (Mutch and Williams 2006;Godin et al, 2007;Scollon et al, 2009). However, when the relative abundance of the different isoforms is taken into account, the predominant hepatic Cyp enzymes (Cyp1a2, Cyp2c50, and Cyp3a11) are all considerably reduced during the course of gestation, especially at GD14.…”

“…Based on the data presented here, the mouse orthologs of CYP2C19, 2c50, and 2c54 were decreased significantly throughout pregnancy, which might suggest that pregnant women may have reduced capacity to metabolize certain PYRs. Hydrolysis of PYRs by CES enzymes has been demonstrated by the urinary metabolite profile following low-dose administration in human volunteers (Eadsforth et al, 1988, Woollen et al, 1992 and in human purified CES (Godin et al, 2007). Human CES1 and 2 hydrolyze the central ester bond to produce two moieties, each of which has no known neurotoxic properties (Gaughan et al, 1976).…”

“…As with chlorpyrifos, this increased susceptibility is hypothesized to be the result of immature detoxication enzymes, including various CYPs and CESs (Tornero-Velez et al, 2010). Various CYP isoforms are capable of contributing to the metabolism of a wide variety of PYR, including CYP2C19, which was the most active human isoform against several PYRs (Godin et al, 2007). Based on the data presented here, the mouse orthologs of CYP2C19, 2c50, and 2c54 were decreased significantly throughout pregnancy, which might suggest that pregnant women may have reduced capacity to metabolize certain PYRs.…”

Metabolism of Pyrethroids by Mosquito Cytochrome P450 Enzymes: Impact on Vector Control

“…These results suggest that differences in metabolic activities among P450 enzymes in insects could be attributed to structural differences resulting in selectivity and different enzymatic activities against insecticides. In human, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 have been reported abilities to metabolize both type I and II pyrethroids (Godin et al, 2007;Scollon et al, 2009). The preference for type I pyrethroid in CYP6AA3 is similar to human CYP2C9 and CYP2C19, while similar metabolic activity toward both types of pyrethroids found for CYP6P7 is similar to that of human CYP2C8 enzyme (Scollon et al, 2009).…”