Cited by 18Carcinogens and Genotoxicity AssessmentWater Treatment and DisinfectionCancer and biochemical research

Mechanisms of oxidative stress-induced in vivo mutagenicity by potassium bromate and nitrofurantoin

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Tsuchiya, Takuma, Kijima, Aki, Ishii, Yuji, Takasu, Shinji, Yokoo, Yuh, Nishikawa, Akiyoshi, Yanai, Tokuma, Umemura, Takashi·2018·Journal of Toxicologic Pathology

Abstract

Oxidative stress is well known as a key factor of chemical carcinogenesis. However, the actual role of oxidative stress in carcinogenesis, such as oxidative stress-related in vivo mutagenicity, remains unclear. It has been reported that 8-hydroxydeoxyguanosine (8-OHdG), an oxidized DNA lesion, might contribute to chemical carcinogenesis. Potassium bromate (KBrO3) and nitrofurantoin (NFT) are known as renal carcinogens in rats. Our previous studies showed an increase in mutant frequencies accompanied by an increased level of 8-OHdG in the kidneys of rodents following KBrO3 or NFT exposure. Furthermore, KBrO3 and NFT induced different types of gene mutations. Thus, in the present study, we performed reporter gene mutation assays and 8-OHdG measurements following KBrO3 or NFT exposure using Nrf2-proficient and Nrf2-deficient mice to clarify the relationship between KBrO3- or NFT-induced oxidative stress and subsequent genotoxicity. Administration of 1,500 ppm of KBrO3 in drinking water resulted in an increase in deletion mutations accompanied by an increase in 8-OHdG level, and administration of 2,500 ppm of NFT in diet induced an increase in guanine base substitution mutations without elevation of the 8-OHdG level in Nrf2-deficient mice. These results demonstrated that the formation of 8-OHdG, which resulted from the oxidizing potential of KBrO3, was directly involved in the increase in deletion mutations, although factors related to oxidative stress other than 8-OHdG might be crucial for NFT-induced guanine base substitution mutations. The present study provides new insight into oxidative stress-related in vivo mutagenicity.

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  1. [20]IARC Working Group on the Evaluation of the Carcinogenic Risk to Humans Nitrofurantoin. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Vol. 50. Lyon. 211–231. 1990.

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Authors
Tsuchiya, T., Kijima, A., Ishii, Y., Takasu, S., Yokoo, Y., Nishikawa, A., Yanai, T., & Umemura, T.
Affiliations
  • National Institute of Health Sciences (JP)
  • Gifu University (JP)
  • Yamazaki University of Animal Health Technology (JP)
Corresponding author
Umemura, Takashi
Venue
Journal of Toxicologic Pathology
Published
2018
Volume
31
Issue
3
Pages
179-188
ISSN
  • 0914-9198 (ISSN-L)
  • 1881-915X
OpenAlex
W2806142935
Cited by
18
References
41
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 1
FWCI
0.23
Type
journal article
Language
en
Open access
Locations
  • Journal of Toxicologic Pathology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Water Treatment and Disinfection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords
oxidative stress, in vivo mutagenicity, potassium bromate, nitrofurantoin, 8-hydroxy-2'-deoxyguanosine, Nrf2, renal carcinogenesis, deletion mutations, genotoxicity, chemical carcinogenesis, Nrf2-deficient mice

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