An evaluation of the redox cycling potencies of paraquat and nitrofurantoin in microsomal and lung slice systems.
The redox cycling abilities of the pulmonary toxins paraquat and nitrofurantoin have been compared with those of the potent redox cyclers, diquat and menadione in lung and liver microsomes by using the oxidation of NADPH and consumption of oxygen. The relative potencies of these compounds to undergo redox cycling were in the order: diquat approximately menadione much greater than paraquat congruent to nitrofurantoin. This was partly attributed to the much lower affinity (Km) of lung and liver microsomes for paraquat and nitrofurantoin than for diquat and menadione. The potential to redox cycle was assessed in an intact cellular system by determining the oxygen consumption of rat lung slices in the presence (10(-6), 10(-5) and 10(-4) M) or absence of each of the four substrates. At concentrations of paraquat (10(-5) M) known to be accumulated by lung slices, a small but significant stimulation of lung slice oxygen uptake was observed. Nitrofurantoin (10(-4)-10(-6) M) did not affect lung slice oxygen uptake in lung slices, an observation consistent with its being a poor redox cycling compound, which is not actively accumulated into lung cells. This data has important implications in assessing the risk of exposure to paraquat. Low levels of paraquat would not be expected to cause lung damage because insufficient compound is present in the lung to exert its toxicity by redox cycling (due to the high Km observed).
Adam
A
A
Department of Pharmacology, School of Pharmacy, University of London, U.K.
Smith
L L
LL
Cohen
G M
GM
D000818:Animals; D004178:Diquat / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009582:Nitrofurantoin / Q000378:metabolism* / Q000633:toxicity; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D010269:Paraquat / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000378:metabolism
D014812:Vitamin K; D009249:NADP; D009582:Nitrofurantoin; D004178:Diquat; D010269:Paraquat; D010100:Oxygen