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)(1) 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 50x background level. The MF (in units of mutants/10(5) 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.
authors.affiliation: Department of Basic Sciences, College of Dentistry, School of Medicine, New York University, New York, NY 10010, USA. joseph.guttenplan@nyu.edu
authors.forename: Joseph
authors.initials: J
authors.lastname: Guttenplan
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Khmelnitsky
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Kosinska
authors.forename: Jeannie
authors.initials: J
authors.lastname: Hennessy
authors.forename: Richard
authors.initials: R
authors.lastname: Bruggeman
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Yuan-Wan
authors.initials: YW
authors.lastname: Sun
authors.forename: Tomas E
authors.initials: TE
authors.lastname: Spratt
authors.forename: Karam
authors.initials: K
authors.lastname: El-Bayoumy
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D016588:Anticarcinogenic Agents; D002273:Carcinogens / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity; D016566:Organoselenium Compounds / Q000494:pharmacology*; D015363:Quinolones / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014059:Tongue; D014062:Tongue Neoplasms / Q000139:chemically induced*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C120195:4-nitroquinolone-1-oxide; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D009153:Mutagens; D016566:Organoselenium Compounds; D015363:Quinolones; D016159:Tumor Suppressor Protein p53; D015112:4-Nitroquinoline-1-oxide; C074153:1,4-phenylenebis(methylene)selenocyanate