Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice

The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase ( gpt ) gene as a target gene are a well-established model system for assessing genotoxicity in vivo . Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2 +/− ::gpt and nrf2 −/− ::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2 -null ( nrf2 −/− ) mice than nrf2 heterozygous ( nrf2 +/− ) and wild-type ( nrf2 +/+ ) mice, whereas in the liver, the mutation frequency was higher in nrf2 −/− and nrf2 +/− mice than in nrf2 +/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo( a )pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2 +/− and nrf2 −/− mice, respectively, compared with BaP-untreated nrf2 +/− mice, showing that nrf2 −/− mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2 +/− mice was substantially different from that in BaP-untreated nrf2 −/− mice. In nrf2 −/− mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt , respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations. [Cancer Res 2007;67(12):5643–8]