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

نویسندگان

  • Sharon R. Spencer
  • Cynthia A. Wilczak
  • Paul Talalay
چکیده

Dimethyl fumarate and dimethyl maléate are potent inducers of cytosolic NAD(P)H:(quinone acceptor) oxidoreductase (here designated uninone reducÃ-ase)activity in Hepa Iclc? murine hepatoma cells in culture, whereas fumarie 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. Nati. Acad. Sci. USA, «5:8261-8265,1988). Dimethyl fumarate also induced quinone reductase in mutants of the Hepa Iclc7 cell line that were either defective in the Ah receptor or in cytochrome 1V45U 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-I mice and female SpragueDawley 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 fumarie acid were only marginally active. The widespread induction of such detoxication enzymes by di methyl 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 en zyme inductions were well tolerated by rodents. Furthermore, the parent fumarie acid has low chronic toxicity and is a naturally occurring meta bolic intermediate that is already in the food chain as an additive, and fumarate salts and esters are used for therapeutic purposes in man.

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تاریخ انتشار 1990