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

摘要

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.