Pyrethroid insecticide lambda-cyhalothrin induces hepatic cytochrome P450 enzymes, oxidative stress and apoptosis in rats
Graphical abstract
Introduction
Lambda-cyhalothrin [α-cyano-3-phenoxybenzyl 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate] is a Type II pyrethroid insecticide with a high level of activity against a wide range of Lepidoptera, Hemiptera, Diptera, and Coleoptera species. Lambda-cyhalothrin has found extensive uses in public and animal health applications as well as in around buildings where it effectively controls a broad spectrum of insects and ectoparasites, including cockroaches, flies, lice, mosquitos, and ticks (Davies et al., 2000; Kroeger et al., 2003). Studies have demonstrated that Type II pyrethroids, that contain an α-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, Anadón et al., 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, Godin et al., 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). Induction of CYP enzymes by Type I and Type II pyrethroids has been demonstrated (Delescluse et al., 1998; Morisseau et al., 1999; Heder et al., 2001; Yang et al., 2009). Although CYP enzymes normally generate metabolites with diminished biologic activity and represent a defense for detoxifying the ROS entities O2 and O22, there are numerous examples where these enzymes catalyze the metabolic activation of chemically inert agents to electrophiles (Ioannides and Parke, 1990; Guengerich et al., 1991; Hinson et al., 1994). The link between P450-mediated metabolism and toxicity of several compounds has been showed (Nyarko et al., 1997; Gonzalez and Gelboin, 1994). Because, to our knowledge, there is limited information on the ability of lambda-cyhalothrin to induce hepatic drug metabolizing enzymes (Yang et al., 2009; Abass et al., 2012), the present study was performed with the objective to establish if lambda-cyhalothrin interacts with microsomal CYP system in rat liver and to analyze whether oxidative stress, proinflammatory and apoptosis mechanisms should be also co-affected by this pyrethroid. To test each of the postulated key events, several parameters were evaluated in the liver of rats following oral pyrethroid exposure: (1) CYP isoform activities, (2) oxidative stress markers (ROS, and enzymatic antioxidant activities), (3) gene expression of proinflammatory (NFκB, IL-1β), oxidative stress and apoptosis (Nrf2, p53, caspase-3, Bax) mediators, and (4) CYP isoform gene expressions and gene expression profile by rat metabolism phase I enzyme PCR array analysis.
Section snippets
Chemicals and reagents
Lambda-cyhalothrin (mixture 1:1 of S and R enantiomers); molecular formula C23H19ClF3NO3. CAS No: 91465-08-6, purity 98.8% w/w were provided by Zeneca Agrochemicals (Syngenta), Bracknell, Berks, England. Aniline, aminopyrine, erythromycin, lauric acid, ethoxy- and pentoxy-resorufin, testosterone, 6β- and 16α-hydroxytestosterone, NADPH, coenzyme A (CoA), all cofactors, bovine serum albumin, sodium azide, glutathione reductase, GSSG, 1-chloro-2,4-dinitrobenzene (CDNB), XTT, xanthine, xanthine
Results
Oral doses of 1, 2, 4 and 8 mg lambda-cyhalothrin/kg bw, for 6 days, did not cause mortality in animals. All animals were observed twice daily (a.m. before treatment and p.m. after treatment). Rats were observed for their general condition of the skin and fur, eyes, nose, oral cavity, abdomen and external genitalia, evaluated for respiration and palpated for masses. Any visible injury, i.e., any clinical signs of dysfunction were observed in any of the animals treated with lambda-cyhalothrin at
Discussion
To our knowledge, this is the first study to show that short-term oral administration of the Type II pyrethroid lambda-cyhalothrin to rats significantly induces hepatic CYP enzymes. This work assess also if there is a correlation of lambda-cyhalothrin effects between hepatic CYP mRNA levels and CYP enzymes activities. The use of mRNA expression profiling increases the throughput and information on the potential of a compound to induce drug metabolizing enzymes. Our data support that there is a
Conclusion
The present study demonstrates, in liver microsomes from rats treated orally with lambda-cyhalothrin, an induction of CYP1A, CYP2E, CYP2B CYP3A and CYP4A subfamilies, results confirmed analyzing mRNA expression by real-time PCR, where mainly CYP2B2 was overexpressed. IPA analysis also showed that several signaling pathways including Oxidative ethanol degradation III, and Fatty acid α-oxidation maybe closely related to adaptive response after lambda-cyhalothrin exposure. Because of the worldwide
Acknowledgements
This work was supported by Project (ALIBIRD-CM Program) Ref. S2013/ABI-2728 from Comunidad de Madrid, and Project Ref. RTA2015-00010-C03-03 from Ministerio de Economía, Industria y Competitividad, Spain.
Conflict of interest
The authors declare that there are no conflicts of interest.
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