The action of paraquat and diquat on the respiration of liver cell fractions

Gage, J. C.

doi:10.1042/bj1090757

Cited by 192 publications

(50 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This activity was not inhibited by cyanide or antimycin A, indicating that the actions of paraquat were not dependent on mitochondrial respiration. These data are consistent with redox cycling of paraquat (14,17). Increases in oxygen utilization by paraquat in lung epithelial cells were inhibited by DPI, indicating that redox cycling occurs via an FAD-dependent enzyme.…”

Section: Discussionsupporting

confidence: 80%

“…Previous studies have suggested that paraquat-induced redox cycling occurs via cytochrome P450 reductase (3,14,62). In contrast, our findings demonstrate that cells overexpressing this enzyme do not display increased oxygen uptake when compared with non-overexpressing parental cells, indicating that cytochrome P450 reductase is not a major contributor to paraquat-induced changes in cellular oxygen flux.…”

Section: Discussioncontrasting

confidence: 55%

See 1 more Smart Citation

Paraquat Increases Cyanide-insensitive Respiration in Murine Lung Epithelial Cells by Activating an NAD(P)H:Paraquat Oxidoreductase

Gray¹,

Heck

Mishin

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pulmonary fibrosis is one of the most severe consequences of exposure to paraquat, an herbicide that causes rapid alveolar inflammation and epithelial cell damage. Paraquat is known to induce toxicity in cells by stimulating oxygen utilization via redox cycling and the generation of reactive oxygen intermediates. However, the enzymatic activity mediating this reaction in lung cells is not completely understood. Using self-referencing microsensors, we measured the effects of paraquat on oxygen flux into murine lung epithelial cells. Paraquat (10 -100 M) was found to cause a 2-4-fold increase in cellular oxygen flux. The mitochondrial poisons cyanide, rotenone, and antimycin A prevented mitochondrial-but not paraquat-mediated oxygen flux into cells. In contrast, diphenyleneiodonium (10 M), an NADPH oxidase inhibitor, blocked the effects of paraquat without altering mitochondrial respiration. NADPH oxidases, enzymes that are highly expressed in lung epithelial cells, utilize molecular oxygen to generate superoxide anion. We discovered that lung epithelial cells possess a distinct cytoplasmic diphenyleneiodonium-sensitive NAD(P)H:paraquat oxidoreductase. This enzyme utilizes oxygen, requires NADH or NADPH, and readily generates the reduced paraquat radical. Purification and sequence analysis identified this enzyme activity as thioredoxin reductase. Purified paraquat reductase from the cells contained thioredoxin reductase activity, and purified rat liver thioredoxin reductase or recombinant enzyme possessed paraquat reductase activity. Reactive oxygen intermediates and subsequent oxidative stress generated from this enzyme are likely to contribute to paraquat-induced lung toxicity.Exposure of humans and animals to toxic doses of paraquat (1,1Ј-dimethyl-4,4Ј-bipyridylium) is known to damage the lung leading to pulmonary edema and hypertension, acute respiratory distress syndrome, and progressive lung fibrosis (1). In target cells paraquat undergoes redox cycling which may contribute to its toxic actions. Several mammalian NADPH oxidases have been identified as potential inducers of paraquat redox cycling including cytochrome P450 reductase and nitric-oxide synthase (2, 3). These enzymes generate a reduced paraquat radical that can act as an electron donor (4) (see Reaction 1). Reacting rapidly with molecular oxygen, the paraquat radical recycles back to paraquat and in the process forms highly toxic oxidants including superoxide anion, hydrogen peroxide, hydroxyl radicals, and in the presence of nitric oxide, peroxynitrite (5-7). Cellular damage generated by these oxidants, including lipid peroxidation, may be important in paraquatinduced lung damage (8, 9).Redox cycling reactions are known to consume significant quantities of oxygen (10 -12). In cells, this has the potential to reduce levels of oxygen available for metabolic processes resulting in oxidative stress and toxicity (13). Previous studies have demonstrated that paraquat can stimulate oxygen uptake by microsomes from rat and rabbit liver and rabbit lung as...

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 55%

Paraquat Increases Cyanide-insensitive Respiration in Murine Lung Epithelial Cells by Activating an NAD(P)H:Paraquat Oxidoreductase

Gray¹,

Heck

Mishin

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In 1968, Gage (24) reported that anaerobic incubation of liver microsomes with NADPH (25)(26)(27) and lung (25,28,29) microsomal hydrogen peroxide production, as measured by the conversion of methanol to formaldehyde. These observations again suggested the potential for a two-electron reduction of molecular oxygen catalyzed by paraquat.…”

Section: Mechanisms Of Paraquattoxicity Redox Cycling Of Paraquatmentioning

confidence: 99%

Paraquat: model for oxidant-initiated toxicity.

Bus¹,

Gibson²

1984

Environ Health Perspect

502

238

View full text Add to dashboard Cite

Paraquat, a quaternary ammonium bipyridyl herbicide, produces degenerative lesions in the lung after systemic administration to man and animals. The pulmonary toxicity of paraquat resembles in several ways the toxicity of several other lung toxins, including oxygen, nitrofurantoin and bleomycin. Although a definitive mechanism of toxicity of paraquat has not been delineated, a cyclic single electron reduction/oxidation of the parent molecule is a critical mechanistic event. The redox cycling of paraquat has two potentially important consequences relevant to the development of toxicity: generation of "activated oxygen" (e.g., superoxide anion, hydrogen peroxide, hydroxyl radical) which is highly reactive to cellular macromolecules; and/or oxidation of reducing equivalents (e.g., NADPH, reduced glutathione) necessary for normal cell function. Paraquat-induced pulmonary toxicity, therefore, is a potentially useful model for evaluation of oxidant mechanisms of toxicity. Furthermore, characterization of the consequences of intracellular redox cycling of xenobiotics will no doubt provide basic information regarding the role of this phenomena in the development of chemical toxicity.

show abstract

“…Paraquat, a well-known herbicide, causes severe injury to the lungs and other organs mediated by toxic reactive oxygen species [5,6] as well as lipid peroxidation that may result in cell death. [7,8] ROS as a natural byproduct of the normal metabolisms of oxygen may play important roles in cell signaling.…”

Section: Discussionmentioning

confidence: 99%