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: 3.33). 11/2006; 34(10):1764-71. DOI: 10.1124/dmd.106.010058
Source: PubMed

ABSTRACT 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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    • "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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    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; DOI:10.1016/j.toxlet.2013.04.015 · 3.36 Impact Factor
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    • "We previously demonstrated the pharmacological and toxicological consequences of in situ CYP-mediated metabolism in several extrahepatic targets recognized in laboratory animals (Vences- Mejía et al. 2006; Hernández-Martínez et al. 2007). It was shown that hepatic CYP enzymes metabolize PYR (Manna et al. 2004; Godin et al. 2006; Price et al. 2008), however, CYP modulation in the central nervous system (CNS) by exposure to PYR has received little attention, probably due to the rapid metabolism of non-toxic intermediate compounds in the liver, impeding the effects on the CNS, including CYP induction. The role of CYP in the brain includes diverse functions such as the aromatization of androgens to estrogens, formation of catechols as well as the metabolism of neurotransmitters and xenobiotics (Parmar et al. 2003). "
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    ABSTRACT: The effect of transfluthrin (TF) or D-allethrin (DA) pyrethroid (PYR) vapors, often contained as main ingredients in two commercially available mosquito repellent mats, on cytochrome P450 (CYP) enzymes of rat brain and liver was assessed. Immunodetection of CYP2E1 and CYP3A2 proteins revealed their induction in cerebrum and cerebellum, but not in liver microsomes of rats exposed by inhalation to TF or DA. This overexpression of proteins correlated with an increase of their catalytic activities. The specifically increased expression of CYP isoenzymes, due to PYR exposure in the rat brain, could perturb the normal metabolism of endogenous and xenobiotic compounds and leads to increased risks of neurotoxicity by bioactivation, lipid peroxidation and DNA damage.
    Toxicology mechanisms and methods 11/2011; 22(1):41-6. DOI:10.3109/15376516.2011.591448 · 1.37 Impact Factor
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    • "The substrate specificity of the individual rat intestinal CE isozymes toward pyrethroids is unknown. However, rat ES3 exhibits a high degree of sequence homology with Hydrolase B, which does not hydrolyze trans-permethrin, bioresmethrin or deltamethrin very effectively (Ross et al., 2006; Godin et al., 2006). Therefore, ES3 is unlikely to contribute significantly to pyrethroid hydrolysis. "
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    ABSTRACT: Hydrolytic metabolism of pyrethroid insecticides in humans is one of the major catabolic pathways that clear these compounds from the body. Rodent models are often used to determine the disposition and clearance rates of these esterified compounds. In this study the distribution and activities of esterases that catalyze pyrethroid metabolism have been investigated in vitro using several human and rat tissues, including small intestine, liver and serum. The major esterase in human intestine is carboxylesterase 2 (hCE2). We found that the pyrethroid trans-permethrin is effectively hydrolyzed by a sample of pooled human intestinal microsomes (5 individuals), while deltamethrin and bioresmethrin are not. This result correlates well with the substrate specificity of recombinant hCE2 enzyme. In contrast, a sample of pooled rat intestinal microsomes (5 animals) hydrolyze trans-permethrin 4.5-fold slower than the sample of human intestinal microsomes. Furthermore, it is demonstrated that pooled samples of cytosol from human or rat liver are approximately 2-fold less hydrolytically active (normalized per mg protein) than the corresponding microsomal fraction toward pyrethroid substrates; however, the cytosolic fractions do have significant amounts (approximately 40%) of the total esteratic activity. Moreover, a 6-fold interindividual variation in carboxylesterase 1 protein expression in human hepatic cytosols was observed. Human serum was shown to lack pyrethroid hydrolytic activity, but rat serum has hydrolytic activity that is attributed to a single CE isozyme. We purified the serum CE enzyme to homogeneity to determine its contribution to pyrethroid metabolism in the rat. Both trans-permethrin and bioresmethrin were effectively cleaved by this serum CE, but deltamethrin, esfenvalerate, alpha-cypermethrin and cis-permethrin were slowly hydrolyzed. Lastly, two model lipase enzymes were examined for their ability to hydrolyze pyrethroids. However, no hydrolysis products could be detected. Together, these results demonstrate that extrahepatic esterolytic metabolism of specific pyrethroids may be significant. Moreover, hepatic cytosolic and microsomal hydrolytic metabolism should each be considered during the development of pharmacokinetic models that predict the disposition of pyrethroids and other esterified compounds.
    Toxicology and Applied Pharmacology 06/2007; 221(1):1-12. DOI:10.1016/j.taap.2007.03.002 · 3.63 Impact Factor
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