Induction of glutathione transferases and NAD(P)H

Quinone reductase by fumaric acid derivatives in rodent cells and tissues

Sharon R. Spencer, Cynthia A. Wilczak, Paul Talalay

Research output: Contribution to journalArticle

Abstract

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-I mice and female Sprague-Diwley 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.

Original languageEnglish (US)
Pages (from-to)7871-7875
Number of pages5
JournalCancer Research
Volume50
Issue number24
StatePublished - Dec 15 1990

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NAD(P)H Dehydrogenase (Quinone)
Glutathione Transferase
NAD
Rodentia
CD-I
Protective Agents
Fumarates
Enzyme Induction
Food Chain
Cytochromes
Hepatocellular Carcinoma
Carcinogenesis
Esters
Cell Culture Techniques
Salts
Dimethyl Fumarate
fumaric acid
Diet
Cell Line
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Induction of glutathione transferases and NAD(P)H : Quinone reductase by fumaric acid derivatives in rodent cells and tissues. / Spencer, Sharon R.; Wilczak, Cynthia A.; Talalay, Paul.

In: Cancer Research, Vol. 50, No. 24, 15.12.1990, p. 7871-7875.

Research output: Contribution to journalArticle

Spencer, Sharon R. ; Wilczak, Cynthia A. ; Talalay, Paul. / Induction of glutathione transferases and NAD(P)H : Quinone reductase by fumaric acid derivatives in rodent cells and tissues. In: Cancer Research. 1990 ; Vol. 50, No. 24. pp. 7871-7875.
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