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

Abstract

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.

Antioxidant Action of Ellagic Acid Ameliorates Paraquat-Induced A549 Cytotoxicity

“…1) It is well established that PQ induces toxicity mainly through its metabolism and subsequent generation of reactive oxygen species (ROS) by redox cycling. 2) Toxicity is severe in the lung due to accumulation of PQ against a concentration gradient. 3) Ellagic acid (EA) is a natural polyphenol that is abundant as ellagitannins in raspberries, strawberries, grapes, and nuts.…”