TY - JOUR
T1 - Synergistic interactions between nadph-cytochrome P-450 reductase, paraquat, and iron in the generation of active oxygen radicals
AU - Clejan, Liviu
AU - Cederbaum, Arthur I.
N1 - Funding Information:
Actl-nowledgements--These studies were supported by U.S.P.H.S. Grant AA-03312 from the National Institute an Alcohol Abuse and Alcoholism. We thank MS Roslgn C. King for typing the manuscript.
PY - 1989/6/1
Y1 - 1989/6/1
N2 - The toxicity associated with paraquat is believed to involve the generation of active oxygen radicals and the production of oxidative stress. Paraquat can be reduced by NADPH-cytochrome P-450 reductase to the paraquat radical; this results in consumption of NADPH. A variety of ferric complexes, including ferric-ATP, -citrate, -EDTA, ferric diethylenetriamine pentaacetic acid and ferric ammonium sulfate, produced a synergistic increase in the paraquat-mediated oxidation of NADPH. This synergism could be observed with very low concentrations of iron, e.g. 0.25 μM ferric-ATP. Very low rates of hydroxyl radical were generated by the reductase with paraquat alone, or with ferric-citrate or -ATP or ferric ammonium sulfate in the absence of paraquat; however, synergistic increases in the rate of hydroxyl radical generation occurred when these ferric complexes were added together with paraquat. Ferric-EDTA and -DTPA catalyzed some production of hydroxyl radicals, which was also synergistically elevated in the presence of paraquat. Ferric desferrioxamine was essentially inert in the absence or presence of paraquat. This enhancement of hydroxyl radical generation was sensitive to catalase and competitive scavengers but not to superoxide dismutase. The interaction of paraquat with NADPH-cytochrome P-450 reductase and ferric complexes resulted in an increase in oxygen radical generation, and various ferric complexes increased the catalytic effectiveness and potentiated significantly the toxicity of paraquat via this synergistic increase in oxygen radical generation by the reductase.
AB - The toxicity associated with paraquat is believed to involve the generation of active oxygen radicals and the production of oxidative stress. Paraquat can be reduced by NADPH-cytochrome P-450 reductase to the paraquat radical; this results in consumption of NADPH. A variety of ferric complexes, including ferric-ATP, -citrate, -EDTA, ferric diethylenetriamine pentaacetic acid and ferric ammonium sulfate, produced a synergistic increase in the paraquat-mediated oxidation of NADPH. This synergism could be observed with very low concentrations of iron, e.g. 0.25 μM ferric-ATP. Very low rates of hydroxyl radical were generated by the reductase with paraquat alone, or with ferric-citrate or -ATP or ferric ammonium sulfate in the absence of paraquat; however, synergistic increases in the rate of hydroxyl radical generation occurred when these ferric complexes were added together with paraquat. Ferric-EDTA and -DTPA catalyzed some production of hydroxyl radicals, which was also synergistically elevated in the presence of paraquat. Ferric desferrioxamine was essentially inert in the absence or presence of paraquat. This enhancement of hydroxyl radical generation was sensitive to catalase and competitive scavengers but not to superoxide dismutase. The interaction of paraquat with NADPH-cytochrome P-450 reductase and ferric complexes resulted in an increase in oxygen radical generation, and various ferric complexes increased the catalytic effectiveness and potentiated significantly the toxicity of paraquat via this synergistic increase in oxygen radical generation by the reductase.
UR - http://www.scopus.com/inward/record.url?scp=0024392071&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(89)90412-7
DO - 10.1016/0006-2952(89)90412-7
M3 - Article
C2 - 2500125
AN - SCOPUS:0024392071
SN - 0006-2952
VL - 38
SP - 1779
EP - 1786
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -