Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones

Patricia Egner, Thomas W Kensler, Tory Prestera, Paul Talalay, Adam H. Libby, H. Howard Joyner, Thomas J. Curphey

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Abstract

4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several other dithiolethiones protect against the acute toxicities of many xenobiotics and are effective inhibitors of experimental carcinogenesis. These protective effects are mediated, in part, through elevation of glutathione S-transferase, NAD(P)H:quinone reductase and UDP-glucuronosyltransferase activities in the liver and other target tissues. The induction of these phase 2 enzymes by oltipraz results from enhanced transcription. In the present study, the molecular mechanisms of these inductions were analyzed utilizing a construct containing a 41 bp enhancer element derived from the 5'-upstream region of the mouse liver glutathione S-transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into murine Hepa 1c1c7 hepatoma cells, the concentrations of 25 dithiolethiones and related analogs required to double growth hormone production were determined and spanned a range nearly three orders of magnitude. Concentrations of dithiolethiones required to double the specific activity of NAD(P)H:quinone reductase were also determined in Hepa 1c1c7 cells. There was a positive correlation (r = 0.78) between the potencies of the 25 active compounds as inducers of both NAD(P)H:quinone reductase activity and growth hormone production. Moreover, no dithiolethiones were inactive in only one system. It is probable, therefore, that the induction of NAD(P)H:quinone reductase and other phase 2 enzymes by oltipraz and other dithiolethiones is mediated entirely through the 41 bp enhancer element.

Original languageEnglish (US)
Pages (from-to)177-181
Number of pages5
JournalCarcinogenesis
Volume15
Issue number2
StatePublished - Feb 1994

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ASJC Scopus subject areas

  • Cancer Research
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Physiology
  • Behavioral Neuroscience

Cite this

Egner, P., Kensler, T. W., Prestera, T., Talalay, P., Libby, A. H., Joyner, H. H., & Curphey, T. J. (1994). Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones. Carcinogenesis, 15(2), 177-181.