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
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.
Available from: dmd.aspetjournals.org
- "In the liver, both oxidative and hydrolytic pathways can be important, depending on the pyrethroid, and species differences are observed in the preferred route of metabolism in this organ. Unlike the rat, human CES1 plays a predominant role for several pyrethroids (Ross et al. 2006;Godin et al., 2006). Among pyrethroids for which oxidative metabolism is a major contributor, species differences exist in the relative importance of the cytochromes P450 involved. "
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ABSTRACT: Human hepatic carboxylesterase 1 and 2 (CES1 and CES2) are important for the disposition of ester- and amide- bond containing pharmaceuticals and environmental chemicals. CES1 and CES2 ontogeny has not been well characterized; causing difficulty in addressing concerns regarding juvenile sensitivity to adverse outcomes associated with exposure to certain substrates. To characterize postnatal human hepatic CES1 and CES2 expression, microsomal and cytosolic fractions were prepared using liver samples from subjects without liver disease [N=165, 1d-18 yrs]. Proteins were fractionated, detected and quantitated by western blotting. Median microsomal CES1 was lower among samples from subjects < 3 weeks of age (N=36) compared to the rest of the population (N=126; 6.27 vs 17.5 pmoles/mg microsomal protein, respectively; p<0.001; Kruskal Wallis test). Median cytosolic CES1 expression was lowest among samples from individuals between birth and 3 weeks of age (N=36), markedly greater among those from ages 3 weeks to 6 years (N=90), and then modestly greater still among those over 6 years of age (N=36; median values = 4.7, 15.8, and 16.6 pmoles/mg cytosolic protein, respectively; p values <0.001 and 0.05, respectively, Kruskal Wallis test). Median microsomal CES2 expression increased across the same three age groups with median values of 1.8, 2.9, and 4.2 pmoles/mg microsomal protein, respectively (p<0.001, both). For cytosolic CES2, only the youngest age group differed from the two older groups (p<0.001; median values=1.29, 1.93, 2.0, respectively). These data suggest that infants < 3 weeks of age would exhibit significantly lower CES1- and CES2-dependent metabolic clearance compared to older individuals.
Available from: Simone Hasenbein
- "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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ABSTRACT: Laboratory toxicity testing is the primary tool used for surface water environmental risk assessment; however, there are critical information gaps regarding the sublethal effects of pesticides. In 10-day exposures, we assessed the lethal and sublethal (motility and growth) toxicities of four commonly used pesticides, bifenthrin, permethrin, cyfluthrin, and chlorpyrifos, on two freshwater invertebrates, Chironomus dilutus and Hyalella azteca. Pyrethroids were more toxic than the organophosphate chlorpyrifos in both species. Bifenthrin was most toxic to H. azteca survival and growth. Cyfluthrin was most toxic to C. dilutus. However, cyfluthrin had the greatest effect on motility on both H. azteca and C. dilutus. The evaluated concentrations of chlorpyrifos did not affect C. dilutus motility or growth, but significantly impacted H. azteca growth. Motility served as the most sensitive endpoint in assessing sublethal effects at low concentrations for both species, while growth was a good indicator of toxicity for all four pesticides for H. azteca. The integration of sublethal endpoints in ambient water monitoring and pesticide regulation efforts could improve identification of low-level pesticide concentrations that may eventually cause negative effects on food webs and community structure in aquatic environments.
Available from: Bülent Kaya
- "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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ABSTRACT: In this study, the genotoxic effects of four synthetic pyrethroids (cypermethrin, cyphenothrin,
deltamethrin, and permethrin) alone and their combinations with different rates of piperonyl butoxide
(PBO) were studied using the wing somatic mutation and recombination test (SMART) of the Drosophila
melanogaster. In the first stage, lethal concentration values (LC25 or LC50) of the synthetic pyrethroids and
concentrations of PBO used for the synthetic pyrethroids were determined. Then, Drosophila larvae were
exposed to lethal concentrations of synthetic pyrethroids and combinations with different rates of PBO
(1:0.25, 1:0.5, 1:0.75, 1:1, and 1:2). According to the obtained results, alone and with the PBO of the
mixtures of the four synthetic pyrethroids are not genotoxic when compared with the negative control. In
addition, the PBO when used alone demonstrated negative results when exposed to 1, 5, and 25 ppm
concentrations, while demonstrating positive result when exposed to 50 ppm concentration. However, the
PBO did not show any co-genotoxic activity with the four tested synthetic pyrethroids. Results of this study
will take an important place in human and environmental health with the new results for the PBO ratios
in insecticide formulations
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