The organoselenium compound 1,4-phenylenebis(methylene)selenocyanate inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorgenesis and enhances glutathione-related antioxidant levels in A/J mouse lung

Chem Biol Interact. 2006 Jun 10;161(2):93-103. doi: 10.1016/j.cbi.2006.03.005. Epub 2006 Mar 12.

Abstract

Selenium, in the form of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) but not Se-enriched yeast (Se-yeast), was highly effective at inhibiting lung tumors induced by the tobacco specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice and at reducing NNK-induced DNA methylation and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the lung. Our goal was to determine if p-XSC but not Se-yeast is effective at inducing levels of glutathione (GSH)-related antioxidants and reducing markers of GSH oxidation in the NNK-induced lung tumor model. In the first bioassay, 6-week-old mice were fed either control or experimental diets (containing 10 ppm as selenium from p-XSC or Se-yeast) and, beginning at 8 weeks of age, received NNK (3 micromol) by gavage once weekly for 8 weeks. After 18 weeks, p-XSC significantly reduced NNK-induced tumor burden by 74% (10.4 +/- 6.0 versus 2.7 +/- 1.5 tumors/mouse, P < 0.001) and tumor incidence from 96% to 68% (P < 0.01), whereas, Se-yeast had no effect. Lung GSH levels were unchanged by either NNK or Se-yeast, but were increased 70% in mice treated with both NNK and p-XSC (P < 0.01) and 41% in mice treated with p-XSC alone. In the second bioassay, the time course of effects of p-XSC was examined. As early as one week after initiation of p-XSC feeding lung and blood selenium levels were increased nearly six- and two-fold, respectively. Increases of 120% for GSH and 65% for Cys were observed in p-XSC groups compared to controls within one week after initiation of p-XSC feeding (P < 0.01). The levels of protein-bound:free GSH ratios and Cys ratios were significantly decreased in p-XSC-treated mice, regardless of NNK status, suggesting a decrease in the levels of oxidative stress. Altogether, these results indicate that p-XSC is a potent inducer of GSH and related thiol antioxidants in the lung leading to decreased levels of oxidative stress and suggest that p-XSC inhibits tumor formation, in part, by protecting against oxidative damage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animal Feed
  • Animals
  • Antioxidants / metabolism*
  • Ascorbic Acid / metabolism
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cysteine / metabolism
  • Disulfides / metabolism
  • Female
  • Glutathione / metabolism*
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Mice
  • Molecular Structure
  • Nitrosamines / chemistry
  • Nitrosamines / pharmacology*
  • Organoselenium Compounds / chemistry
  • Organoselenium Compounds / pharmacology*
  • Selenium / blood
  • Selenium / pharmacokinetics
  • Selenium / pharmacology
  • Sulfhydryl Compounds / metabolism
  • Time Factors
  • Yeasts

Substances

  • Antioxidants
  • Disulfides
  • Nitrosamines
  • Organoselenium Compounds
  • Sulfhydryl Compounds
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • 1,4-phenylenebis(methylene)selenocyanate
  • Glutathione
  • Selenium
  • Cysteine
  • Ascorbic Acid