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

Abstract

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.

miR-200a Regulates Nrf2 Activation by Targeting Keap1 mRNA in Breast Cancer Cells

“…In these cancers, it is thought that hijacking of detoxifying pathways, through constitutive hyperactivation of Nrf2, promotes resistance to chemotherapy. Nevertheless, in support of a protective role for Nrf2, several studies have found that Nrf2-deficient mouse models show increased carcinogen sensitivity and cancer incidence (12)(13)(14)(15). Furthermore, other studies suggest additional roles for Nrf2 in opposing tumorigenesis.…”

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

“…A recent thoughtful analysis by Forman et al concluded that there is neither evidence nor likelihood that redox regulation is directly mediated by any of the fast reacting oxygencentered or other radicals that may arise from chain reactions initiated by the primary physiological radicals (134). Their persuasive, if not convincing, argument is that aggressive radicals such as OH, RO , or halogen radicals derived from the myeloperoxidase reaction, which react with almost all kind of biomolecules at nearly diffusion-limited rate constants 8 ) and binds to its effector, the responsive element in the DNA, and allows the RNA polymerase (RNAP) to effect gene expression that removes the signal via enhanced alkyl hydroperoxide reductase (AhpC/AhpF) synthesis, thus terminating or modulating the sensing process. Prevention or termination of transduction is also achieved by reducing oxidized OxyR by glutaredoxin A (GrxA).…”

“…They comprise enzymes that directly or indirectly exert antioxidant functions (5,21,111,202,264,373,491), molecular chaperons (265), and proteins that enhance GSH synthesis and regeneration (164,174,210,276,330,336), phase 2 detoxication, drug metabolism (169,210,326,392,424,479), recognition, repair, and removal of damaged proteins (191,264,265,393), and nucleotide excision repair (8), further proteins that regulate the expression of other transcription factors, growth factors, and receptors (113,163), and inhibit cytokine-mediated inflammation (6,209,245,385,503) and autophagy (394). With its broad range of target genes, Nrf2 is certainly one of the most important transcription factors that protect the organism against exogenous stressors, be they poisonous food ingredients, physical damage, or infection.…”

La voie Nrf2 en pathologie respiratoire

“…Ainsi, les gènes codant pour des antioxydants sont diminués dans l'épithélium pulmonaire de patients fumeurs atteints de cancer [34]. Une susceptibilité accrue de l'ADN aux mutations spontanées et induites par le benzopyrène dans le poumon de souris Nrf2 -/-a été rapportée [35]. De même, la diminution de la protection contre le cancer observée chez des souris Nrf2 -/-en restriction calorique suggère que la plupart des effets bénéfiques de la restriction calorique sur les processus de carcinogenèse empruntent la voie Nrf2 [36].…”