Evidence for energy-dependent accumulation of paraquat into rat lung

Rose, Michael S.; Smith, Lewis L.; Wyatt, I. J.

doi:10.1038/252314b0

Cited by 274 publications

(87 citation statements)

References 7 publications

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“…Nonetheless, these investigators questioned whether lipid peroxidation was a primary mechanistic event in paraquat toxicity because an analogous agent which is not highly toxic to the lung, diquat, was even more potent than paraquat in stimulating lipid peroxidation. This conclusion is confounded, however, by the observation that paraquat, and not diquat, is accumulated in lung cells (most likely by Type I and/or Type II) by an apparent active transport mechanism (73). These investigators also reported that pretreatment of mice with an antioxidant, N, N'-diphenyl-p-phenylenediamine, or a high carbohydrate diet prevented in vitro paraquat stimulation of lung microsomal lipid peroxidation (74).…”

Section: Paraquat-induced Lipid Peroxidationmentioning

confidence: 99%

Paraquat: model for oxidant-initiated toxicity.

Bus¹,

Gibson²

1984

Environ Health Perspect

502

238

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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.

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Section: Paraquat-induced Lipid Peroxidationmentioning

confidence: 99%

Paraquat: model for oxidant-initiated toxicity.

Bus¹,

Gibson²

1984

Environ Health Perspect

502

238

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“…In summary, PQ is accumulated in Type I and Type II alveolar epithelial cells by an energy-dependent system (13). Although PQ is a poor redox cycler, its concentration in target cells predisposes these cells to toxicity, dependent on the balance of prooxidant to antioxidant enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…However, DQ causes minimal lung damage in cases of intoxication, probably because of the absence of an uptake system for its accumulation into the lungs (13).…”

Section: Introductionmentioning

confidence: 99%

An Assessment of the Role of Redox Cycling in Mediating the Toxicity of Paraquat and Nitrofurantoin

Adam

Smith

Cohen

1990

Environmental Health Perspectives

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The abilities of paraquat, diquat, and nitrofurantoin to undergo cyclic oxidation and reduction with rat microsomal systems have been assessed and compared to that of the potent redox cycler, menadione. Diquat and menadione were found to be potent redox cyclers with comparable abilities to elicit a nonstoichiometric increase in both the consumption of 02 and the oxidation of NADPH, compared to the amounts of substrate added. In contrast, paraquat and nitrofurantoin redox cycled poorly, being an order of magnitude less potent than either diquat or menadione. This was reflected in kinetic studies using lung and liver microsomes, which showed that NADPH-cytochrome P-450 reductase had a lower affinity (Km) for paraquat and nitrofurantoin than for menadione and diquat, although values of Vmax were comparable for all the substrates except nitrofurantoin, which was lower.In order to assess redox cycling of the substrates in an intact lung system, the 02 consumption of rat lung slices was measured in the presence of all four compounds. A small increase in lung slice 02 Uptake was observed with paraquat (10 -6 M) in the first 2.5 hr of incubation, possibly because of redox cycling of a high intracellular concentration of paraquat resulting from active accumulation into target cells. This stimulation in 02 uptake was no longer observed when slices were incubated for a longer period or with higher paraquat concentrations (10 -4 M), possibly because of toxic effects in target cells.High concentrations of diquat (10 -c M) had no effect on 02 consumption of lung slices. These results together with the poor ability to redox cycle with microsomes and the absence of a specific uptake system highlight the problem of associating redox cycling and oxidative stress in the mechanism of nitrofurantoin toxicity.

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“…In order to investigate the accumulation of paraquat into lung, Rose et al (9) studied its uptake into rat lung slices. Using this method, they found that paraquat was accumulated in a time-dependent manner into slices by a process that was energy-dependent and obeyed saturation kinetics (9).…”

Section: Introductionmentioning

confidence: 99%

“…Using this method, they found that paraquat was accumulated in a time-dependent manner into slices by a process that was energy-dependent and obeyed saturation kinetics (9). Consequently, it is possible to derive an apparent Km of 70 uM and a Vmax of 300 nmole paraquat/g lung hr (9). The (8).…”

Section: Introductionmentioning

confidence: 99%

The Importance of Epithelial Uptake Systems in Lung Toxicity

Smith¹,

Lewis²,

Wyatt³

et al. 1990

Environmental Health Perspectives

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The discovery that the herbicide paraquat was selectively accumulated by the lung, both in vivo and in vitro, in comparison with other tissues, provided an explanation for its selective toxicity to the lung. This uptake process is energy dependent and obeys saturation kinetics. A characterization ofthe process led to the identification of endogenous chemicals that are the natural substrates for the system. Among these are a series of diamines and polyamines, as well as the diaminodisulfide cystamine. It appears that paraquat, because of specific structural similarities to these endogenous polyamines, is mistakenly accumulated by the lung. This uptake process is specifically located in the alveolar Type II cell, the Clara cell, and probably the alveolar Type I cell.With the development of knowledge of the structural requirements of chemicals to be accumulated by this system, it is possible to predict which chemicals will be accumulated by the lung or design molecules that are targeted to the alveolar epithelial and Clara cells.In the wider perspective, this polyamine uptake system has been found on a number of cancerous cells or tissues. With the knowledge of the uptake system in the lung, it should be possible to design drugs that will be specifically concentrated in cells that possess this system. IntroductionBecause the lung is responsible for all gas exchange necessary for oxidative metabolism, it is inevitably exposed to toxic gases, vapors, and particles (if small enough) present in the atmosphere. The respiratory function of the lung requires a large surface area (in man, about the size of a tennis court) that, on the air side, is covered by epithelial cells intimately associated with an extensive capillary network. Apart from inhalation, the lung is also exposed to toxic compounds that have been absorbed into the bloodstream or are in the form of metabolites, formed either in the lung or in extrapulmonary tissue.In order to meet its respiratory function, the lung requires numerous cell types. More than 40 cell types have been identified in the lung (1); these are required to provide the diverse architecture associated with cartilage, smooth muscle, connective tissue, submucosal glands, the vascular system, and the respiratory unit (alveoli)

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Evidence for energy-dependent accumulation of paraquat into rat lung

Cited by 274 publications

References 7 publications

Paraquat: model for oxidant-initiated toxicity.

Paraquat: model for oxidant-initiated toxicity.

An Assessment of the Role of Redox Cycling in Mediating the Toxicity of Paraquat and Nitrofurantoin

The Importance of Epithelial Uptake Systems in Lung Toxicity

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