Transcriptional responses to oxidative stress: pathological and toxicological implications

The utilization of molecular oxygen as the terminal electron acceptor for energy production has in many ways shaped the evolution of complex life, physiology, and certain disease processes. The generation of reactive oxygen species (ROS), either as by-products of O(2) metabolism or by specialized enzymes, has the potential to damage cellular components and functions. Exposure to a variety of exogenous toxicants also promotes ROS production directly or through indirect means to cause toxicity. Oxidative stress activates the expression of a wide range of genes that mediate the pathogenic effect of ROS or are required for the detection and detoxification of the oxidants. In many cases, these are mediated by specific transcription factors whose expression, structure, stability, nuclear targeting, or DNA-binding affinity is regulated by the level of oxidative stress. This review examines major transcription factors that mediate transcriptional responses to oxidative stress, focusing on recent progress in the signaling pathways and mechanisms of activation of transcription factors by oxidative stress and the implications of this regulation in the development of disease and chemical toxicity.