skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment

Abstract

Highlights: •Low-dose MNNG pretreatment suppresses high-dose MNNG induced in vitro transformation. •Gastric ulcers induced by high-dose MNNG decreased after low-dose MNNG pretreatment. •Efficacy of low-dose MNNG related to resistance of mutation and oxidative stress. -- Abstract: Exposure to mild stress by chemicals and radiation causes DNA damage and leads to acquired stress resistance. Although the linear no-threshold (LNT) model of safety assessment assumes risk from any dose, evidence from radiological research demonstrates a conflicting hormetic phenomenon known as the hormesis effect. However, the mechanisms underlying radiation hormesis have not yet been clarified, and little is known about the effects of low doses of chemical carcinogens. We analyzed the efficacy of pretreatment with low doses of the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on the subsequent induction of cell transformation and gastric ulceration by high-dose MNNG. We used an in vitro Balb/3T3 A31-1-1 cell transformation test and monitored the formation of gastric ulcers in 5-week-old male ICR mice that were administered MNNG in drinking water. The treatment concentrations of MNNG were determined by the cell survival rate and past reports. For low-dose in vitro and in vivo experiments, MNNG was used at 0.028 μM, and 2.8 μg/mL, respectively. The frequency of cell transformationmore » induced by 10 μm MNNG was decreased by low-dose MNNG pretreatment to levels similar to that of spontaneous transformation. In addition, reactive oxygen species (ROS) and mutation frequencies induced by 10 μm MNNG were decreased by low-dose MNNG pretreatment. Importantly, low-dose MNNG pretreatment had no effect on cell proliferation. In vivo studies showed that the number of gastric ulcers induced by 1 mg/mL MNNG decreased after low-dose MNNG pretreatment. These data indicate that low-dose pretreatment with carcinogens may play a beneficial role in the prevention of chemical toxicity under specified conditions.« less

Authors:
 [1];  [2];  [3]; ; ; ;  [1]
  1. Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871 (Japan)
  2. (Japan)
  3. Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 (Japan)
Publication Date:
OSTI Identifier:
22239632
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 435; Journal Issue: 4; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALKYLATING AGENTS; BIOLOGICAL ADAPTATION; CARCINOGENS; CELL PROLIFERATION; CELL TRANSFORMATIONS; CONCENTRATION RATIO; DMSO; DOSES; DRINKING WATER; GLUTATHIONE; GUANINE; IN VITRO; IN VIVO; INHIBITION; ION CYCLOTRON-RESONANCE; MICE; MUTATION FREQUENCY; OXYGEN; RISK ASSESSMENT; ULCERS

Citation Formats

Onodera, Akira, E-mail: onodera@pharm.kobegakuin.ac.jp, Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Kawai, Yuichi, Kashimura, Asako, Ogita, Fumiya, Tsutsumi, Yasuo, and Itoh, Norio. Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment. United States: N. p., 2013. Web. doi:10.1016/J.BBRC.2013.05.049.
Onodera, Akira, E-mail: onodera@pharm.kobegakuin.ac.jp, Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Kawai, Yuichi, Kashimura, Asako, Ogita, Fumiya, Tsutsumi, Yasuo, & Itoh, Norio. Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment. United States. doi:10.1016/J.BBRC.2013.05.049.
Onodera, Akira, E-mail: onodera@pharm.kobegakuin.ac.jp, Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Kawai, Yuichi, Kashimura, Asako, Ogita, Fumiya, Tsutsumi, Yasuo, and Itoh, Norio. Fri . "Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment". United States. doi:10.1016/J.BBRC.2013.05.049.
@article{osti_22239632,
title = {Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment},
author = {Onodera, Akira, E-mail: onodera@pharm.kobegakuin.ac.jp and Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 and Kawai, Yuichi and Kashimura, Asako and Ogita, Fumiya and Tsutsumi, Yasuo and Itoh, Norio},
abstractNote = {Highlights: •Low-dose MNNG pretreatment suppresses high-dose MNNG induced in vitro transformation. •Gastric ulcers induced by high-dose MNNG decreased after low-dose MNNG pretreatment. •Efficacy of low-dose MNNG related to resistance of mutation and oxidative stress. -- Abstract: Exposure to mild stress by chemicals and radiation causes DNA damage and leads to acquired stress resistance. Although the linear no-threshold (LNT) model of safety assessment assumes risk from any dose, evidence from radiological research demonstrates a conflicting hormetic phenomenon known as the hormesis effect. However, the mechanisms underlying radiation hormesis have not yet been clarified, and little is known about the effects of low doses of chemical carcinogens. We analyzed the efficacy of pretreatment with low doses of the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on the subsequent induction of cell transformation and gastric ulceration by high-dose MNNG. We used an in vitro Balb/3T3 A31-1-1 cell transformation test and monitored the formation of gastric ulcers in 5-week-old male ICR mice that were administered MNNG in drinking water. The treatment concentrations of MNNG were determined by the cell survival rate and past reports. For low-dose in vitro and in vivo experiments, MNNG was used at 0.028 μM, and 2.8 μg/mL, respectively. The frequency of cell transformation induced by 10 μm MNNG was decreased by low-dose MNNG pretreatment to levels similar to that of spontaneous transformation. In addition, reactive oxygen species (ROS) and mutation frequencies induced by 10 μm MNNG were decreased by low-dose MNNG pretreatment. Importantly, low-dose MNNG pretreatment had no effect on cell proliferation. In vivo studies showed that the number of gastric ulcers induced by 1 mg/mL MNNG decreased after low-dose MNNG pretreatment. These data indicate that low-dose pretreatment with carcinogens may play a beneficial role in the prevention of chemical toxicity under specified conditions.},
doi = {10.1016/J.BBRC.2013.05.049},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 435,
place = {United States},
year = {Fri Jun 14 00:00:00 EDT 2013},
month = {Fri Jun 14 00:00:00 EDT 2013}
}