Introduction to serial reviews: physiological relevance of antioxid/redox genes; learning from genetically modified animals.

When organisms evolve to the point of using oxygen, the fight against oxygen toxicity begins, and it becomes a matter of survival. While oxygen respiration enables the utilization of a large body of free energy stored in organic compounds, the reactive oxygen species (ROS) that are an inevitable result of the respiratory reaction, and other metabolic processes, are believed to cause various diseases and to hasten aging. To understand the oxidative stress and redox regulation of human beings, investigations based on the chemical reactions to biological responses are a prerequisite. While experiments involving chemical reactions in vitro are essential to understanding the molecular basis of oxidative stress, biological responses can be elucidated by ex vivo studies, such as cell culture, and by in vivo studies using animals. Although most results obtained from studies performed under ex vivo conditions are consistent with those from in vivo studies, sometime inconsistencies emerge. Such discrepancies could, at least in part, be attributed to oxygen conditions during experiments as well as to the complexity of biological systems.

In most cases, cell and tissue cultures are performed in an incubator that is maintained at 5% CO2 and 95% air that contains atmospheric (21%) oxygen. Because oxygen concentrations within the body are maintained at 2–5% in peripheral tissues, oxygen concentrations during culturing will be higher by approximately one order. This indicates that cells/tissues in culture will be hyper oxygenated, which puts them under chronic oxidative stress. Antioxidative/redox proteins are induced to eliminate ROS in cells that survive these hyperoxic conditions, and they are maintained at high levels compared to in vivo situations. Therefore, to elucidate the functions of antioxidants and genes involved in antioxidation/redox reactions, the ideal situation would be to perform in vitro studies under oxygen conditions that compare to the physiologic state.

Advances in the technology of recombinant DNA now enable the generation of genetically modified animals on demand, which can provide clues for direct investigations into the roles of genes in vivo. Despite metabolic rates between human and laboratory animals that are quite different, the genes involved are essentially the same. Thus, information obtained from these animals is limited but still helpful in understanding human physiology and pathogenesis. Limitations that result in ambiguities from in vivo study alone could be partly overcome by employing cells isolated from genetically modified mice, such as mouse embryonic fibroblast (MEF). Thus, the usefulness of mice in the study of gene functions is expanding.

This serial review represents an overview of recent advances in pivotal genes that are responsible for antioxidation, ROS production, and redox reaction, extending to transcriptional regulatory factors that are involved in gene expression. Because recent studies have become more specialized, a comprehensive perspective is often missed in the research field. An overview of pivotal genes from the molecular basis of genetically modified animals provides an opportunity to revisit those genes, and leads to a total understanding of them in living organisms. This kind of information would be especially beneficial for researchers doing clinical work, but would also be helpful for those engaged in basic research.