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 wks after the start of 4-NQO. For studies on p53 levels, rats were euthanized at 11, 15 and 23 wks. 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/10 5 plaque forming units) for the 7, 12 and 23 week 4-NQO groups were respectively, 184 ± 88, 237 ± 105, 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-NQOalone 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.

A robust method for assessing chemically induced mutagenic effects in the oral cavity of transgenic Big Blue® rats

“…In that study, the MF was 39.1 ± 7.5 × 10 −6 (19%) in gingiva/buccal tissues and 49.8 ± 17.8 × 10 −6 (36%) in gingiva/palate tissues. In the absence of other historical control MF data for these unique tissues, the background MFs and variance are comparable to reported results in the tongue of BB rats (42 ± 12 × 10 −6 (29%) [Guttenplan et al, ], and also that in other somatic tissues, e.g. 43.4 ± 8.8 × 10 −6 (20%) in liver and 29.7 ± 14.3 × 10 −6 (48%) in bone marrow, as reported by Young et al [] and 51.1 ± 19.9 × 10 −6 (39%) and 38.1 ± 9.1 × 10 −6 (25%), respectively, as reported here (Supporting Information Table SI).…”

“…Vehicle control animals (0 ppm) and test article‐treated animals (10 ppm 4‐NQO) were dosed ad libitum via drinking water in an amber glass bottle from Day 1 until Day 29. The dose of 4‐NQO was the same as that used by Guttenpan et al [] and Ohne et al [] which showed it to be mutagenic and carcinogenic at this dose, respectively. Animals were observed twice daily at least 6 hr apart for moribundity and mortality.…”

Effect of Selenium on Carbimazole-Induced Histopathological and Histochemical Alterations in Prostate of Albino Rats

“…Yu et al [34] concluded that 0.1 mg/kg selenium(Na 2 SeO 3 ) inhibited oxidative stress, apoptosis and cell cycle changes induced by excess fluoride in kidney of rats. Guttenplan et al [35] showed that the organoselenium compound, 1,4-phenylenebis (methylene) selenocyanate inhibited 4-nitroquinoline-N-oxide-induced tongue tumorigenesis and DNA damage in the tongue of Fisher rats. Kara et al [36] reported that selenium protected rat testes against cadmium-induced oxidative damage.…”

Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates

“…1) for the new compounds described here. The following characteristics were taken into consideration: (1) Molecular symmetry, as a broad concept, because this is a structural property that is frequently present in many cytotoxic drugs [29] and some reported sulfur [24e28] and selenium derivatives have this property [6,9,13]. (2) A central scaffold consisting of a methyl imidothiocarbamate (methylisothiourea) or methyl (methylselenourea) and benzyl (benzylselenourea) imidoselenocarbamates connected by a carbonyl group onto two identical lateral heteroaromatic rings.…”