Species Differences in the in Vitro Metabolism of Deltamethrin and Esfenvalerate: Differential Oxidative and Hydrolytic Metabolism by Humans and Rats

ArticleinDrug Metabolism and Disposition 34(10):1764-71 · November 2006with28 Reads
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.
    • "In human liver, two predominant and highly expressed carboxylesterases have been identified and are termed hepatic carboxylesterase-1 (hCE-1) and hepatic carboxylesterase-2 (hCE-2) (Brzezinski et al., 1994; Pindel et al., 1997). Differential activity between these two isozymes have been reported for deltamethrin and esfenvalerate, with hCE1 having a higher hydrolytic specific activity towards these two pyrethroids (Godin et al., 2006). Ross et al. (2006) observed both isozymes have a higher activity toward transpermethrin than cis-permethrin. "
    [Show abstract] [Hide abstract] ABSTRACT: Human exposure to multiple pyrethroid insecticides may occur because of their broad use on crops and for residential pest control. To address the potential health risk from co-exposure to pyrethroids, it is important to understand their disposition and toxicity in target organs such as the brain, and surrogates such as the blood when administered as a mixture. The objective of this study was to assess the correlation between blood and brain concentrations of pyrethroids and neurobehavioral effects in the rat following an acute oral administration of the pyrethroids as a mixture. Male Long-Evans rats were administered a mixture of β-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate and _cis_- and _trans_-permethrin in corn oil at seven dose levels. The pyrethroid with the highest percentage in the dosing solution was _trans_-permethrin (31% of total mixture dose) while deltamethrin and esfenvalerate had the lowest percentage (3%). Motor activity of the rats was then monitored for 1 h. At 3.5 h post-dosing, the animals were euthanized and blood and brain were collected. These tissues were extracted and analyzed for parent pyrethroid using HPLC-tandem mass spectrometry. Cypermethrin and _cis_-permethrin were the predominate pyrethroids detected in blood and brain, respectively, at all dosage levels. The relationship of total pyrethroid concentration between blood and brain was linear (r2 = 0.87). The pyrethroids with the lowest fraction in blood were _trans_-permethrin and β-cyfluthrin and in brain were deltamethrin and esfenvalerate. The relationship between motor activity of the treated rats and summed pyrethroid blood and brain concentration was described using a sigmoidal Emax model with the Effective Concentration50 being more sensitive for brain than blood. The data suggests summed pyrethroid rat blood concentration could be used as a surrogate for brain concentration as an aid to study the neurotoxic effects of pyrethroids administered as a mixture under the conditions used in this study.
    Article · Jun 2016
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jan 2016
    • "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). "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Mar 2015
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