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

Research output: Contribution to journalArticle

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

Fingerprint

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

Keywords

  • 4-NQO
  • Chemoprevention
  • Cll
  • Mutagenesis
  • Oral
  • p-XSC
  • Selenium

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Genetics

Cite this

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

In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 634, No. 1-2, 01.12.2007, p. 146-155.

Research output: Contribution to journalArticle

Guttenplan, Joseph ; Chen, Kun Ming ; Khmelnitsky, Michael ; Kosinska, Wieslawa ; Hennessy, Jeannie ; Bruggeman, Richard ; Desai, Dhimant ; Amin, Shantu ; Sun, Yuan Wan ; Spratt, Tomas E. ; El-Bayoumy, Karam. / 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. In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. 2007 ; Vol. 634, No. 1-2. pp. 146-155.
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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.",
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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

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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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