Role of cytochrome P450 reductase in nitrofurantoin-induced redox cycling and cytotoxicity.

Free Radical Biology & Medicine
Yun WangJeffrey D Laskin

Abstract

The one-electron reduction of redox-active chemotherapeutic agents generates highly toxic radical anions and reactive oxygen intermediates (ROI). A major enzyme catalyzing this process is cytochrome P450 reductase. Because many tumor cells highly express this enzyme, redox cycling of chemotherapeutic agents in these cells may confer selective antitumor activity. Nitrofurantoin is a commonly used redox-active antibiotic that possesses antitumor activity. In the present studies we determined whether nitrofurantoin redox cycling is correlated with cytochrome P450 reductase activity and cytotoxicity in a variety of cell lines. Recombinant cytochrome P450 reductase was found to support redox cycling of nitrofurantoin and to generate superoxide anion, hydrogen peroxide, and, in the presence of redox-active iron, hydroxyl radicals. This activity was NADPH dependent and inhibitable by diphenyleneiodonium, indicating a requirement for the flavin cofactors in the reductase. Nitrofurantoin-induced redox cycling was next analyzed in different cell lines varying in cytochrome P450 reductase activity including Chinese hamster ovary cells (CHO-OR) constructed to overexpress the enzyme. Nitrofurantoin-induced hydrogen peroxide production was 1...Continue Reading

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Citations

May 27, 2010·Molecular Cancer Therapeutics·Yun WangJeffrey D Laskin
May 23, 2009·Cancer Science·Shinae Kizaka-Kondoh, Hideko Konse-Nagasawa
Feb 18, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·John T SzilagyiJeffrey D Laskin
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Jul 22, 2016·Annals of the New York Academy of Sciences·Yi-Hua JanJeffrey D Laskin
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