An assessment of the role of redox cycling in mediating the toxicity of paraquat and nitrofurantoin.
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 O2 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 O2 consumption of rat lung slices was measured in the presence of all four compounds. A small increase in lung slice O2 uptake was observed with paraquat (10(-5) 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 O2 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(-5) M) had no effect on O2 consumption of lung slices.(ABSTRACT TRUNCATED AT 250 WORDS)
Adam
A
A
Toxicology Unit, School of Pharmacy, University of London, UK.
Smith
L L
LL
Cohen
G M
GM
D000818:Animals; D004178:Diquat / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009582:Nitrofurantoin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010269:Paraquat / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D011726:Pyridinium Compounds / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000378:metabolism / Q000493:pharmacokinetics
D011726:Pyridinium Compounds; D014812:Vitamin K; D009582:Nitrofurantoin; D004178:Diquat; D010269:Paraquat