Mechanism of cytotoxicity of paraquat

Fukushima, Tetsuhito; Tanaka, Keiko; Lim, Heejin; Moriyama, Masaki

doi:10.1265/ehpm.2002.89

Cited by 89 publications

(71 citation statements)

References 69 publications

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“…2 The abbreviations used are: PQ, paraquat ( 4 Cl (all w/v), pH 5.5, NaOH), YPD (1% (w/v) yeast extract, 2% (w/v) peptone, 2% (w/v) glucose), and YPG (1% (w/v) yeast extract, 2% (w/v) peptone, 3% (v/v) glycerol). For plates, liquid media were supplemented with 2% (w/v) agar.…”

Section: Methodsmentioning

confidence: 99%

“…7B). The EPR signal of the SO 2 . radical in the dithionite solution did not interfere with quantitation of the PQ .…”

Section: Methodsmentioning

confidence: 99%

“…2C). The damage to mtDNA was due to O 2 . within the mitochondrial matrix, as PQ only increased the formation of petite colonies in the ⌬sod2 yeast strain and not the wild type (Fig.…”

Section: Pq Increases Mitochondrial Matrix O 2 Within Intact Yeast-mentioning

confidence: 99%

“…Paraquat (1,1Ј-dimethyl-4,4Ј-bipyridinium dichloride; PQ) 2 is used to increase superoxide (O 2 . ) flux when investigating oxidative stress (reviewed in Refs.…”

mentioning

confidence: 99%

“…Therefore the interaction of PQ with mitochondria is an important component of its toxicity, and PQ is used in experimental models of Parkinson disease to generate mitochondrial oxidative damage (30). Consequently, there is considerable interest in identifying the sites of PQ 2ϩ reduction associated with mitochondria and in determining whether O 2 .…”

mentioning

confidence: 99%

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Complex I Is the Major Site of Mitochondrial Superoxide Production by Paraquat

Cochemé

Murphy

2008

Journal of Biological Chemistry

500

375

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Paraquat (1,1-dimethyl-4,4-bipyridinium dichloride) is widely used as a redox cycler to stimulate superoxide production in organisms, cells, and mitochondria. This superoxide production causes extensive mitochondrial oxidative damage, however, there is considerable uncertainty over the mitochondrial sites of paraquat reduction and superoxide formation. Here we show that in yeast and mammalian mitochondria, superoxide production by paraquat occurs in the mitochondrial matrix, as inferred from manganese superoxide dismutase-sensitive mitochondrial DNA damage, as well as from superoxide assays in isolated mitochondria, which were unaffected by exogenous superoxide dismutase. This paraquat-induced superoxide production in the mitochondrial matrix required a membrane potential that was essential for paraquat uptake into mitochondria. This uptake was of the paraquat dication, not the radical monocation, and was carrier-mediated. Experiments with disrupted mitochondria showed that once in the matrix paraquat was principally reduced by complex I (mammals) or by NADPH dehydrogenases (yeast) to form the paraquat radical cation that then reacted with oxygen to form superoxide. Together this membrane potential-dependent uptake across the mitochondrial inner membrane and the subsequent rapid reduction to the paraquat radical cation explain the toxicity of paraquat to mitochondria.Paraquat (1,1Ј-dimethyl-4,4Ј-bipyridinium dichloride; PQ) 2 is used to increase superoxide (O 2 . ) flux when investigating oxidative stress (reviewed in Refs. 1 and 2). The paraquat dication (PQ 2ϩ ) accepts an electron from a reductant to form the paraquat monocation radical (PQ . . and regenerate PQ 2ϩ (Fig. 1A). This redox cycling is a proximal cause of PQ toxicity, as indicated by the protection against PQ by superoxide dismutase (SOD) overexpression or administration of SOD mimetics (4 -8), and by the PQ hypersensitivity caused by SOD deficiency (9 -11).PQ has been used to generate O 2 . in systems ranging from isolated mitochondria (12-15) and cultured mammalian cells (4,14,16,17), to whole organisms including Saccharomyces cerevisiae (18 -21), Caenorhabditis elegans (22, 23), Drosophila melanogaster (9, 24 -26), and rodents (6,11,27). In many of these studies, PQ increases mitochondrial oxidative damage; for example, mitochondrial expression of human peroxiredoxin 5 protects yeast more effectively against PQ toxicity than expression in the cytosol (19); flies overexpressing catalase in mitochondria are resistant to PQ, whereas enhancement of cytosolic catalase was not protective (24); RNA interference silencing of MnSOD (the isoform of superoxide dismutase located in the mitochondrial matrix) in flies causes hypersensitivity to PQ (9), mice heterozygous for MnSOD show greater sensitivity to PQ than wild-type (11), and mitochondrial swelling is one of the earliest ultrastructural changes upon PQ exposure in vivo (28,29). Therefore the interaction of PQ with mitochondria is an important component of its toxicity, and PQ is used in expe...

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Section: Methodsmentioning

confidence: 99%

“…7B). The EPR signal of the SO 2 . radical in the dithionite solution did not interfere with quantitation of the PQ .…”

Section: Methodsmentioning

confidence: 99%

“…2C). The damage to mtDNA was due to O 2 . within the mitochondrial matrix, as PQ only increased the formation of petite colonies in the ⌬sod2 yeast strain and not the wild type (Fig.…”

Section: Pq Increases Mitochondrial Matrix O 2 Within Intact Yeast-mentioning

confidence: 99%

“…Paraquat (1,1Ј-dimethyl-4,4Ј-bipyridinium dichloride; PQ) 2 is used to increase superoxide (O 2 . ) flux when investigating oxidative stress (reviewed in Refs.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Complex I Is the Major Site of Mitochondrial Superoxide Production by Paraquat

Cochemé

Murphy

2008

Journal of Biological Chemistry

500

375

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EFFECT OF LOW DOSES OF HERBICIDE PARAQUAT ON ANTIOXIDANT DEFENSE IN Drosophila

Krůček

Korandová

Šerý

et al. 2015

Arch Insect Biochem Physiol

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Despite a high toxicity, paraquat is one of the most widely used herbicides in the world. Our study evaluated the effect of paraquat exposure on antioxidant response and locomotion activity in Drosophila melanogaster. We examined the enzymatic activity of superoxide dismutase (SOD) and catalase, and the transcript levels of both enzymes. Flies were exposed to a wide range of paraquat concentrations (0.25 μM to 25 mM) for 12 h. SOD, at both transcript and enzymatic levels, revealed a biphasic dose-response curve with the peak at 2.5 μM paraquat. A similar dose-response curve was observed at transcript levels of catalase. Males revealed higher susceptibility to paraquat exposure, displaying higher lethality, increased levels of SOD activity, and increased peroxide levels than in females. We found that the exposure of females to 2.5 μM paraquat leads to an increase in locomotion activity. Because susceptibility to paraquat was enhanced by mating, the study supports the hypothesis of elevation of stress sensitivity as a physiological cost of reproduction.

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RBE4 cells are highly resistant to paraquat‐induced cytotoxicity: studies on uptake and efflux mechanisms

Vilas-Boas

Silva

Pinho

et al. 2013

J of Applied Toxicology

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Paraquat (PQ) is a widely used, highly toxic and non-selective contact herbicide, which has been associated with central neurotoxic effects, namely the development of Parkinson's disease, but whose effects to the blood-brain barrier (BBB) itself have rarely been studied. This work studied the mechanisms of PQ uptake and efflux in a rat's BBB cell model, the RBE4 cells. PQ is believed to enter cells using the basic or neutral amino acid or polyamine transport systems or through the choline-uptake system. In contrast, PQ efflux from cells is reported to be mediated by P-glycoprotein. Therefore, we evaluated PQ-induced cytotoxicity and the effect of some substrates/blockers of these transporters (such as arginine, L-valine, putrescine, hemicholinium-3 and GF120918) on such cytotoxicity. RBE4 cells were shown to be extremely resistant to PQ after 24 h of exposure; even at concentrations as high as 50 mM approximately 45% of the cells remained viable. Prolonging exposure until 48 h elicited significant cytotoxicity only for PQ concentrations above 5 mM. Although hemicholinium-3, a choline-uptake system inhibitor, significantly protected cells against PQ-induced toxicity, none of the effects were observed for arginine, L-valine or putrescine. Meanwhile, inhibiting the efflux pump P-glycoprotein using GF120918 significantly enhanced PQ-induced cytotoxicity. In conclusion, PQ used the choline-uptake system, instead of the transporters for the basic or neutral amino acids or for the polyamines, to enter RBE4 cells. P-glycoprotein extrudes PQ back to the extracellular medium. However, this efflux mechanism only partially explains the observed RBE4 resistance to PQ.

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Mechanism of cytotoxicity of paraquat

Cited by 89 publications

References 69 publications

Complex I Is the Major Site of Mitochondrial Superoxide Production by Paraquat

Complex I Is the Major Site of Mitochondrial Superoxide Production by Paraquat

EFFECT OF LOW DOSES OF HERBICIDE PARAQUAT ON ANTIOXIDANT DEFENSE IN Drosophila

RBE4 cells are highly resistant to paraquat‐induced cytotoxicity: studies on uptake and efflux mechanisms

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