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.

19 Reads
  • Source
    • "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.
    Environmental Science and Pollution Research 03/2015; 22(15). DOI:10.1007/s11356-015-4374-1 · 2.83 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
    Ekoloji 09/2014; 23(92):9-18. DOI:10.5053/ekoloji.2014.922 · 0.61 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine. Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats. Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at β phase. Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine. These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system. In order to confirm, a second experiment was carried out. We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days). At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily. Liver and kidney were susceptible to cyfluthrin-dependent induction of 12- and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction. Also cyfluthrin increased the β-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator. In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress.
    Toxicology Letters 04/2013; 220(2). DOI:10.1016/j.toxlet.2013.04.015 · 3.26 Impact Factor
Show more