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.
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.
Richie
John P
JP
Department of Health Evaluation Sciences, Penn State Cancer Institute, Penn State University, Milton S. Hershey Medical Center, PA 17033, USA.
Kleinman
Wayne
W
Desai
Dhimant H
DH
Das
Arunangshu
A
Amin
Shantu G
SG
Pinto
John T
JT
El-Bayoumy
Karam
K
D000821:Animal Feed; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D015394:Molecular Structure; D009602:Nitrosamines / Q000737:chemistry / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012643:Selenium / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors; D015003:Yeasts
D000975:Antioxidants; D004220:Disulfides; D009602:Nitrosamines; D016566:Organoselenium Compounds; D013438:Sulfhydryl Compounds; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C074153:1,4-phenylenebis(methylene)selenocyanate; D005978:Glutathione; D012643:Selenium; D003545:Cysteine; D001205:Ascorbic Acid