Absence of P-Glycoprotein Transport in the Pharmacokinetics and Toxicity of the Herbicide Paraquat

Lacher, Sarah E.; Gremaud, Julia N.; Skagen, Kasse; Steed, Emily; Dalton, Rachel; Sugden, Kent D.; Cardozo-Pelaez, Fernando; Sherwin, Catherine M.T.; Woodahl, Erica L.

doi:10.1124/jpet.113.209791

Cited by 18 publications

(22 citation statements)

References 57 publications

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“…3) (diazinon, dieldrin, endosulfan, maneb, MPP 1 , and rotenone). Doxorubicin and colchicine data have been previously reported (Lacher et al, 2014). To confirm that differences in sensitivities between LLC-vector and LLC-MDR1-WT cells were due to P-gp, we used the P-gp inhibitors GF120918 and verapamil.…”

Section: Resultsmentioning

confidence: 85%

Section: Methodsmentioning

confidence: 99%

“…Sensitivity to cytotoxic agents was evaluated in LLC-vector and LLC-MDR1-WT cells as previously described (Lacher et al, 2014) using the CellTiter-Glo cell viability assay (Promega, Fitchburg, WI). Cells were plated overnight at a density of 1000 cells/well in 96-well plates and grown in the presence of test compounds for 72 hours at 37°C (Lacher et al, 2014). Cells were treated with the following pesticides over a wide concentration range: diazinon (11-1000 mM), dieldrin (4-1000 mM), endosulfan (0.4-100 mM), maneb (0.16-200 mM), MPP 1 (0.46-3000 mM), rotenone (0.76-5000 nM), and ivermectin (0.4-35 mM).…”

Section: Methodsmentioning

confidence: 99%

“…Inhibition of R123 efflux in LLC-vector and LLC-MDR1-WT cells was performed based on a previously developed assay (Woodahl et al, 2004;Lacher et al, 2014). Concentration ranges of the following pesticides were experimentally determined based on solubility and to minimize cell death: diazinon (7-500 mM), dieldrin (3-200 mM), endosulfan (3-200 mM), maneb (1-250 mM), MPP 1 (1-1000 mM), rotenone (1-100 mM), and ivermectin (0.05-50 mM).…”

Section: Methodsmentioning

confidence: 99%

“…Pesticides are a diverse class of compounds with different mechanisms of action, pharmacokinetic properties, and uses, i.e., fungicides, herbicides, and insecticides (Hatcher et al, 2008;Goldman, 2014;Chin-Chan et al, 2015). We reported previously that P-gp does not transport paraquat (Lacher et al, 2014). Our current study is not an exhaustive screen of P-gp transport of pesticides, but rather a focused evaluation of pesticides most commonly associated with Parkinson's disease: diazinon, dieldrin, endosulfan, maneb, MPP 1 , and rotenone (Hatcher et al, 2008;Goldman, 2014;Chin-Chan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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P-Glycoprotein Transport of Neurotoxic Pesticides

Lacher

Skagen

Veit

et al. 2015

J Pharmacol Exp Ther

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P-glycoprotein (P-gp) has been associated with a number of neurodegenerative diseases, including Parkinson's disease, although the mechanisms remain unclear. Altered transport of neurotoxic pesticides has been proposed in Parkinson's disease, but it is unknown whether these pesticides are P-gp substrates. We used three in vitro transport models, stimulation of ATPase activity, xenobiotic-induced cytotoxicity, and inhibition of rhodamine-123 efflux, to evaluate P-gp transport of diazinon, dieldrin, endosulfan, ivermectin, maneb, 1-methyl-4-phenyl-4-phenylpyridinium ion (MPP 1 ), and rotenone. Diazinon and rotenone stimulated ATPase activity in P-gp-expressing membranes, with V max values of 22.4 6 2.1 and 16.8 6 1.0 nmol inorganic phosphate/min per mg protein, respectively, and K m values of 9.72 6 3.91 and 1.62 6 0.51 mM, respectively, compared with the P-gp substrate verapamil, with a V max of 20.8 6 0.7 nmol inorganic phosphate/min per mg protein and K m of 0.871 6 0.172 mM. None of the other pesticides stimulated ATPase activity. We observed an increased resistance to MPP 1 and rotenone in LLC-MDR1-WT cells compared with LLC-vector cells, with 15.4-and 2.2-fold increases in EC 50 values, respectively. The resistance was reversed in the presence of the P-gp inhibitor verapamil. None of the other pesticides displayed differential cytotoxicity. Ivermectin was the only pesticide to inhibit P-gp transport of rhodamine-123, with an IC 50 of 0.249 6 0.048 mM. Our data demonstrate that dieldrin, endosulfan, and maneb are not P-gp substrates or inhibitors. We identified diazinon, MPP 1 , and rotenone as P-gp substrates, although further investigation is needed to understand the role of P-gp transport in their disposition in vivo and associations with Parkinson's disease.

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Section: Resultsmentioning

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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P-Glycoprotein Transport of Neurotoxic Pesticides

Lacher

Skagen

Veit

et al. 2015

J Pharmacol Exp Ther

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Cycloartenyl Ferulate Inhibits Paraquat‐Induced Apoptosis in HK‐2 Cells With the Involvement of ABCC1

Hong

Liu

Zhao

et al. 2015

J of Cellular Biochemistry

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Nephrotoxicity induced by chemicals such as paraquat (PQ) is a common clinical phenomenon; therefore, searching for drugs with renal protective effect is of a great practical significance. Our previous investigation found that cycloartenyl ferulate (CF) can antagonize the cytotoxic effect of PQ, and recent studies also revealed a variety of bioactivities of CF. However, specific molecular mechanisms underlying the protective effect of CF have not been explored yet. HPLC detection of PQ content indicated that CF reduced PQ accumulation in HK-2 cells and thereby improved cell survival. Western blot results showed that both PQ and CF did not affect the expression of ABCB1; however, while PQ suppressed the expression of ABCC1, CF upregulated ABCC1 expression and thereby reversed the inhibitory effect of PQ on ABCC1 expression. Meanwhile, HK-2 cells did not express ABCG2. When the expression of ABCC1 was knocked down with siRNA, the inhibitory effect of CF on intracellular PQ accumulation was blocked. Further flow cytometric analysis showed that while PQ significantly induced the appearance of sub-G1 apoptotic peak in cells, CF evidently inhibited apoptosis. TUNEL-DAPI double-staining also detected that PQ significantly induced the occurrence of DNA fragmentation in cells, whereas CF effectively inhibited the effect of PQ. Further results showed that ABCC1 siRNA effectively abolished the protective effect of CF on PQ-induced apoptosis. Taken together, these data demonstrated that in HK-2 cells, CF could antagonize PQ-induced toxicity with the involvement of regulatiion of ABCC1 protein expression, which provides a new strategy for treatments of nephrotoxicity.

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Implication of human drug transporters to toxicokinetics and toxicity of pesticides

Guéniche

Bruyère

Vée

et al. 2019

Pest Management Science

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Human membrane drug transporters are recognized as major actors of pharmacokinetics. Pesticides also interact with human drug transporters, which may have consequences for pesticide toxicokinetics and toxicity. The present review summarizes key findings about this topic. In vitro assays have demonstrated that some pesticides, belonging to various chemical classes, modulate drug transporter activity, regulate transporter expression and/or are substrates, thus bringing the proof of concept for pesticide‐transporter relationships. The expected low human concentration of pesticides in response to environmental exposure constitutes a key‐parameter to be kept in mind for judging the in vivo relevance of such pesticide‐transporter interactions and their consequences for human health. Existing data about interactions of pesticides with drug transporters remain, however, rather sparse; more extensive and systematic characterization of pesticide‐transporter relationships, through the use of high throughput in vitro assays and/or in silico methods, is, therefore, required. In addition, consideration of transporter polymorphisms, pesticide mixture effects and physiological and pathological factors governing drug transporter expression may help to better define the in vivo relevance of pesticide‐transporter interactions in terms of toxicokinetics and toxicity for humans. © 2019 Society of Chemical Industry

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Absence of P-Glycoprotein Transport in the Pharmacokinetics and Toxicity of the Herbicide Paraquat

Cited by 18 publications

References 57 publications

P-Glycoprotein Transport of Neurotoxic Pesticides

P-Glycoprotein Transport of Neurotoxic Pesticides

Cycloartenyl Ferulate Inhibits Paraquat‐Induced Apoptosis in HK‐2 Cells With the Involvement of ABCC1

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

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