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

Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Drug Metabolism and Disposition (Impact Factor: 3.25). 11/2006; 34(10):1764-71. DOI: 10.1124/dmd.106.010058
Source: PubMed


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 (CL(INT)) 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 CL(INT) 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.

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    • "In addition, the biotransformation capacity of a species to inactivate or activate specifically acting compounds has been considered an important factor causing differences in sensitivity (Chambers and Carr 1995; Escher and Hermens 2002). While both C. dilutus and H. azteca possess cytochrome P450-mediated mono-oxogenases capable of metabolizing organophosphate insecticides (Ankley and Collyard 1995), metabolic enzyme profiles can vary greatly across species (Clark 1989; Godin et al. 2006). As an organophosphate , chlorpyrifos is metabolically activated to a more toxic intermediate, chlorpyrifos-oxon that mainly acts on the nervous system by inhibiting acetylcholinesterase (ACh), leading to continuous neurotransmission, acute cholinergic syndrome, and eventually paralysis and death (Hsieh et al. 2001). "
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    • "Epidemiological data and investigations in rodents have shown that pyrethroids undergo metabolism by carboxylesterases and cytochrome P450 enzyme systems (Anand et al. 2006, Godin et al. 2006, Ross et al. 2006, Crow et al. 2007, Godin et al. 2007). Hydrolysis of pyrethroids is generally considered a detoxification process (Casida et al. 1983, Cantalamessa 1993). "
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    Ekoloji 09/2014; 23(92):9-18. DOI:10.5053/ekoloji.2014.922 · 0.61 Impact Factor
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    • "Studies have demonstrated that pyrethroids, such as cyfluthrin, that contain an ␣-cyano-3-phenoxybenzyl alcohol and a halogen group in the acid moiety, are readily absorbed from the respiratory tract following inhalation (Kavlock et al., 1979) and from the gastrointestinal tract following oral administration (Anadón et al., 1996, 2006) and detoxified by cytochrome P450 (CYP)-mediated oxidation and esterase-mediated hydrolysis followed by conjugation (Ruzo et al., 1979; Shono et al., 1979; Dayal et al., 2003). Studies in vivo and in vitro and epidemiological data have shown that pyrethroids undergo extensive metabolism by carboxylesterases and CYPs (Anand et al., 2006; Godin et al., 2006, 2007; Nishi et al., 2006; Crow et al., 2007; Scollon et al., 2009). High occupational and environmental human exposure to pyrethroid insecticides could interact with the normal metabolism of drugs or xenobiotics (Carlson and Schoening, 1980; Catinot et al., 1989). "
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