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

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Wang Y, Gray JP, Mishin V, Heck DE, Laskin DL, Laskin JD

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

Free Radic Biol Med. 2008 Mar 15;44(6):1169-79. doi: 10.1016/j.freeradbiomed.2007.12.013. Epub 2007 Dec 23.

PubMed ID

18206659 [ View in PubMed

]

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 16-fold greater in lysates from CHO-OR cells than from control CHO cells. A strong correlation between cytochrome P450 reductase activity and nitrofurantoin-induced redox cycling among the cell lines was found. Unexpectedly, no correlation between nitrofurantoin-induced ROI production and cytotoxicity was observed. These data indicate that nitrofurantoin-induced redox cycling and subsequent generation of ROI are not sufficient to mediate cytotoxicity and that cytochrome P450 reductase is not a determinant of sensitivity to redox-active chemotherapeutic agents.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Nitrofurantoin	NADPH--cytochrome P450 reductase	Protein	Humans	Unknown	Substrate	Details