Enhanced NAD(P)H:quinone reductase activity prevents glutamate toxicity produced by oxidative stress.
Glutamate toxicity in the N18-RE-105 neuronal cell line results from the inhibition of high-affinity cystine uptake, which leads to a depletion of glutathione and the accumulation of oxidants. Production of superoxides by one-electron oxidation/reduction of quinones is decreased by NAD(P)H:quinone reductase, an enzyme with DT-diaphorase activity. Using glutamate toxicity in N18-RE-105 cells as a model of neuronal oxidative stress, we report that the degree of glutamate toxicity observed is inversely proportional to quinone reductase activity. Induction of quinone reductase activity by treatment with t-butylhydroquinone reduced glutamate toxicity by up to 80%. In contrast, treatment with the quinone reductase inhibitor dicumarol potentiated the toxic effect of glutamate. Measurement of cellular glutathione indicates that increases in its levels are not responsible for the protective effect of t-butylhydroquinone treatment. Because many types of cell death may involve the formation of oxidants, induction of quinone reductase may be a new strategy to combat neurodegenerative disease.
Murphy
T H
TH
Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
De Long
M J
MJ
Coyle
J T
JT
D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000506:poisoning*; D018698:Glutamic Acid; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006873:Hydroquinones / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D011808:Quinone Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014812:Vitamin K / Q000494:pharmacology
D000975:Antioxidants; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D006873:Hydroquinones; D014812:Vitamin K; D018698:Glutamic Acid; D001728:Dicumarol; C018855:2-tert-butylhydroquinone; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D005978:Glutathione; D019803:Glutathione Disulfide