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Induction of Glutathione Transferases and NAD(P)H:Quinone Reductase by Fumaric Acid Derivatives in Rodent Cells and Tissues¹

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Dimethyl fumarate and dimethyl maleate are potent inducers of cytosolic NAD(P)H:(quinone acceptor) oxidoreductase (here designated quinone reductase) activity in Hepa 1c1c7 murine hepatoma cells in culture, whereas fumaric and maleic acids are much less potent, in agreement with the much greater reactivity of the esters as Michael reaction acceptors (P. Talalay, M. J. De Long, and H. J. Prochaska, Proc. Natl. Acad. Sci. USA, 85: 8261–8265, 1988). Dimethyl fumarate also induced quinone reductase in mutants of the Hepa 1c1c7 cell line that were either defective in the Ah receptor or in cytochrome P₁-450 activity, thereby establishing that this compound is a monofunctional inducer (H. J. Prochaska and P. Talalay, Cancer Res., 48: 4776–4782, 1988). Addition of dimethyl fumarate to the diet of female CD-1 mice and female Sprague-Dawley rats at 0.2–0.5% concentrations elevated cytosolic glutathione transferases and quinone reductase activities in a variety of organs, whereas much higher concentrations of fumaric acid were only marginally active. The widespread induction of such detoxication enzymes by dimethyl fumarate suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophile toxicity. This proposal is supported by the finding that the concentrations of dimethyl fumarate required to obtain substantial enzyme inductions were well tolerated by rodents. Furthermore, the parent fumaric acid has low chronic toxicity and is a naturally occurring metabolic intermediate that is already in the food chain as an additive, and fumarate salts and esters are used for therapeutic purposes in man.

¹ These studies were supported by Grant NIH P01 CA 44530 from the National Cancer Institute, Department of Health and Human Services, and by Special Institutional Grant SIG-3 from the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205.

Received 7/31/90. Accepted 9/18/90.

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