Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide

Joseph Guttenplan, Kun Ming Chen, Michael Khmelnitsky, Wieslawa Kosinska, Jeannie Hennessy, Richard Bruggeman, Dhimant Desai, Shantu Amin, Yuan Wan Sun, Tomas E. Spratt, Karam El-Bayoumy

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Abstract

Previously we showed that the organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (p-XSC)11p-XSC, phenylenebis(methylene)selenocyanate; MF, mutant fraction; 4-NQO, 4-nitroquinoline-N-oxide. inhibits 4-nitroquinoline-N-oxide (4-NQO)-induced tongue tumorigenesis in Fisher rats. Here we investigate possible mechanisms of this inhibition by monitoring mutagenesis and p53 protein levels in lacI and conventional Fisher rats treated with: (1) a carcinogenic dose of 4-NQO for 10 weeks in drinking water, (2) 4-NQO + p-XSC (15 ppm as selenium), and (3) 4-NQO followed by p-XSC. For mutagenesis studies, rats were euthanized at 7, 12 or 23 weeks after the start of 4-NQO. For studies on p53 levels, rats were euthanized at 11, 15 and 23 weeks. Appropriate controls were also monitored. In the 4-NQO-alone groups, the mutant fraction (MF) in the cII gene in tongue increased at least 50× background level. The MF (in units of mutants/105 plaque forming units) for the 7, 12, and 23 weeks 4-NQO groups were respectively, 184 ± 88, 237 ± 105, and 329 ± 110. Thus, mutagenesis increased with length of exposure and post-treatment time. p-XSC modestly (ca. 15-30%) inhibited mutagenesis under all conditions. The inhibition reached significance at the last time point. When p-XSC was administered after 4-NQO, the MF was also modestly reduced. In 4-NQO-alone animals, levels of p53 in tongue (determined by Western blotting) were 1, 1.5 and 2.4 control levels at 10, 15 and 23 weeks, respectively. In the p-XSC + 4-NQO group, the enhancement in p53 levels by 4-NQO treatment was decreased about 90% at 15 weeks and 45% (P < 0.05) at 23 weeks, and by slightly smaller percentages in corresponding post-treatment groups. p-XSC alone did not alter p53 levels. As p53 levels generally increase in response to DNA damage, these results suggest that p-XSC reduces 4-NQO-induced DNA damage, resulting in reduced 4-NQO-induced mutagenesis and carcinogenesis. However, the fact that p-XSC is also effective when administered after 4-NQO, suggests additional mechanisms of inhibition exist.

Original languageEnglish (US)
Pages (from-to)146-155
Number of pages10
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume634
Issue number1-2
DOIs
StatePublished - Dec 1 2007

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4-Nitroquinoline-1-oxide
Tongue
Mutagenesis
Proteins
1,4-phenylenebis(methylene)selenocyanate
DNA Damage
Organoselenium Compounds
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

@article{7144796601af44d7a2d914711a5864c7,
title = "Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide",
abstract = "Previously we showed that the organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (p-XSC)11p-XSC, phenylenebis(methylene)selenocyanate; MF, mutant fraction; 4-NQO, 4-nitroquinoline-N-oxide. inhibits 4-nitroquinoline-N-oxide (4-NQO)-induced tongue tumorigenesis in Fisher rats. Here we investigate possible mechanisms of this inhibition by monitoring mutagenesis and p53 protein levels in lacI and conventional Fisher rats treated with: (1) a carcinogenic dose of 4-NQO for 10 weeks in drinking water, (2) 4-NQO + p-XSC (15 ppm as selenium), and (3) 4-NQO followed by p-XSC. For mutagenesis studies, rats were euthanized at 7, 12 or 23 weeks after the start of 4-NQO. For studies on p53 levels, rats were euthanized at 11, 15 and 23 weeks. Appropriate controls were also monitored. In the 4-NQO-alone groups, the mutant fraction (MF) in the cII gene in tongue increased at least 50× background level. The MF (in units of mutants/105 plaque forming units) for the 7, 12, and 23 weeks 4-NQO groups were respectively, 184 ± 88, 237 ± 105, and 329 ± 110. Thus, mutagenesis increased with length of exposure and post-treatment time. p-XSC modestly (ca. 15-30{\%}) inhibited mutagenesis under all conditions. The inhibition reached significance at the last time point. When p-XSC was administered after 4-NQO, the MF was also modestly reduced. In 4-NQO-alone animals, levels of p53 in tongue (determined by Western blotting) were 1, 1.5 and 2.4 control levels at 10, 15 and 23 weeks, respectively. In the p-XSC + 4-NQO group, the enhancement in p53 levels by 4-NQO treatment was decreased about 90{\%} at 15 weeks and 45{\%} (P < 0.05) at 23 weeks, and by slightly smaller percentages in corresponding post-treatment groups. p-XSC alone did not alter p53 levels. As p53 levels generally increase in response to DNA damage, these results suggest that p-XSC reduces 4-NQO-induced DNA damage, resulting in reduced 4-NQO-induced mutagenesis and carcinogenesis. However, the fact that p-XSC is also effective when administered after 4-NQO, suggests additional mechanisms of inhibition exist.",
author = "Joseph Guttenplan and Chen, {Kun Ming} and Michael Khmelnitsky and Wieslawa Kosinska and Jeannie Hennessy and Richard Bruggeman and Dhimant Desai and Shantu Amin and Sun, {Yuan Wan} and Spratt, {Tomas E.} and Karam El-Bayoumy",
year = "2007",
month = "12",
day = "1",
doi = "10.1016/j.mrgentox.2007.07.005",
language = "English (US)",
volume = "634",
pages = "146--155",
journal = "Mutation Research - Genetic Toxicology and Environmental Mutagenesis",
issn = "1383-5718",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide

AU - Guttenplan, Joseph

AU - Chen, Kun Ming

AU - Khmelnitsky, Michael

AU - Kosinska, Wieslawa

AU - Hennessy, Jeannie

AU - Bruggeman, Richard

AU - Desai, Dhimant

AU - Amin, Shantu

AU - Sun, Yuan Wan

AU - Spratt, Tomas E.

AU - El-Bayoumy, Karam

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Previously we showed that the organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (p-XSC)11p-XSC, phenylenebis(methylene)selenocyanate; MF, mutant fraction; 4-NQO, 4-nitroquinoline-N-oxide. inhibits 4-nitroquinoline-N-oxide (4-NQO)-induced tongue tumorigenesis in Fisher rats. Here we investigate possible mechanisms of this inhibition by monitoring mutagenesis and p53 protein levels in lacI and conventional Fisher rats treated with: (1) a carcinogenic dose of 4-NQO for 10 weeks in drinking water, (2) 4-NQO + p-XSC (15 ppm as selenium), and (3) 4-NQO followed by p-XSC. For mutagenesis studies, rats were euthanized at 7, 12 or 23 weeks after the start of 4-NQO. For studies on p53 levels, rats were euthanized at 11, 15 and 23 weeks. Appropriate controls were also monitored. In the 4-NQO-alone groups, the mutant fraction (MF) in the cII gene in tongue increased at least 50× background level. The MF (in units of mutants/105 plaque forming units) for the 7, 12, and 23 weeks 4-NQO groups were respectively, 184 ± 88, 237 ± 105, and 329 ± 110. Thus, mutagenesis increased with length of exposure and post-treatment time. p-XSC modestly (ca. 15-30%) inhibited mutagenesis under all conditions. The inhibition reached significance at the last time point. When p-XSC was administered after 4-NQO, the MF was also modestly reduced. In 4-NQO-alone animals, levels of p53 in tongue (determined by Western blotting) were 1, 1.5 and 2.4 control levels at 10, 15 and 23 weeks, respectively. In the p-XSC + 4-NQO group, the enhancement in p53 levels by 4-NQO treatment was decreased about 90% at 15 weeks and 45% (P < 0.05) at 23 weeks, and by slightly smaller percentages in corresponding post-treatment groups. p-XSC alone did not alter p53 levels. As p53 levels generally increase in response to DNA damage, these results suggest that p-XSC reduces 4-NQO-induced DNA damage, resulting in reduced 4-NQO-induced mutagenesis and carcinogenesis. However, the fact that p-XSC is also effective when administered after 4-NQO, suggests additional mechanisms of inhibition exist.

AB - Previously we showed that the organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (p-XSC)11p-XSC, phenylenebis(methylene)selenocyanate; MF, mutant fraction; 4-NQO, 4-nitroquinoline-N-oxide. inhibits 4-nitroquinoline-N-oxide (4-NQO)-induced tongue tumorigenesis in Fisher rats. Here we investigate possible mechanisms of this inhibition by monitoring mutagenesis and p53 protein levels in lacI and conventional Fisher rats treated with: (1) a carcinogenic dose of 4-NQO for 10 weeks in drinking water, (2) 4-NQO + p-XSC (15 ppm as selenium), and (3) 4-NQO followed by p-XSC. For mutagenesis studies, rats were euthanized at 7, 12 or 23 weeks after the start of 4-NQO. For studies on p53 levels, rats were euthanized at 11, 15 and 23 weeks. Appropriate controls were also monitored. In the 4-NQO-alone groups, the mutant fraction (MF) in the cII gene in tongue increased at least 50× background level. The MF (in units of mutants/105 plaque forming units) for the 7, 12, and 23 weeks 4-NQO groups were respectively, 184 ± 88, 237 ± 105, and 329 ± 110. Thus, mutagenesis increased with length of exposure and post-treatment time. p-XSC modestly (ca. 15-30%) inhibited mutagenesis under all conditions. The inhibition reached significance at the last time point. When p-XSC was administered after 4-NQO, the MF was also modestly reduced. In 4-NQO-alone animals, levels of p53 in tongue (determined by Western blotting) were 1, 1.5 and 2.4 control levels at 10, 15 and 23 weeks, respectively. In the p-XSC + 4-NQO group, the enhancement in p53 levels by 4-NQO treatment was decreased about 90% at 15 weeks and 45% (P < 0.05) at 23 weeks, and by slightly smaller percentages in corresponding post-treatment groups. p-XSC alone did not alter p53 levels. As p53 levels generally increase in response to DNA damage, these results suggest that p-XSC reduces 4-NQO-induced DNA damage, resulting in reduced 4-NQO-induced mutagenesis and carcinogenesis. However, the fact that p-XSC is also effective when administered after 4-NQO, suggests additional mechanisms of inhibition exist.

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U2 - 10.1016/j.mrgentox.2007.07.005

DO - 10.1016/j.mrgentox.2007.07.005

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EP - 155

JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis

JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis

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