Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

• Published in: Environmental health perspectives 1990-08, Vol.88, p.13-25
• Main Authors: Nebert, Daniel W., Petersen, Daniel D., Fornace, Albert J.
• Format: Article
• Language: English
• Subjects: 560300 - Chemicals Metabolism & Toxicology; ANIMALS; Apoptosis; AROMATICS; BIOLOGICAL STRESS; Carcinogens; CHEMICAL REACTIONS; CHROMOSOMAL ABERRATIONS; Chromosomes; DNA; DNA damage; DNA Damage - genetics; Enzymes; Gene expression regulation; GENE REGULATION; Genes; HYDROCARBONS; MAMMALS; Messenger RNA; Metabolism of Carcinogens; METABOLITES; MICE; MUTATIONS; ORGANIC COMPOUNDS; OXIDATION; Oxidation-Reduction; Oxidative stress; PLANT CELLS; Plant Extracts - toxicity; POLYCYCLIC AROMATIC HYDROCARBONS; Quinones; Quinones - toxicity; RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT; RADIOINDUCTION; RODENTS; Sesquiterpenes; Stress, Physiological - chemically induced; Stress, Physiological - genetics; Stress, Physiological - metabolism; Terpenes; TRANSCRIPTION; VERTEBRATES
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.908813

A major source of oxidative stress in animals is plant stress metabolites, also termed phytoalexins. The aromatic hydrocarbon-responsive [Ah] gene battery is considered here as a model system in which we can study metabolically coordinated enzymes that respond to phytoalexin-induced oxidative stress. In the mouse, the [Ah] battery comprises at least six genes: two Phase I genes, CYP1A1 and CYP1A2; and four Phase II genes, Nmo-1, Aldh-1, Ugt-1, and Gt-1. All six genes appear to be regulated positively by inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other ligands of the Ah receptor. In the absence of foreign inducer, the control of Nmo-1 gene expression is independent of the control of CYP1A1 and CYP1A2 gene expression. The radiation deletion homozygote c14 CoS/c14 CoSmouse is lacking about 1.1 centiMorgans of chromosome 7. Although having no detectable CYP1A1 or CYP1A2 activation, the untreated c14 CoS/c14 CoSmouse exhibits markedly elevated transcripts of the Nmo-1 gene and three growth arrest-and DNA damage-inducible (gadd) genes. These data suggest that the missing region on chromosome 7 in the c14 CoS/c14 CoSmouse contains a gene(s), which we propose to call Nmo-1n, encoding a trans-acting factor(s) that is a negative effector of the Nmo-1 and gadd genes. The three other [Ah] battery Phase II genes behave similarly to Nmo-1 in the c14 CoS/c14 CoSmouse. This coordinated response to oxidative stress and DNA damage, by way of the release of a mammalian battery of genes from negative control, bears an interesting resemblance to the SOS response in bacteria.