Antioxidant therapeutics: Pandora′s box

Evolution has favored the utilization of dioxygen (O₂) in the development of complex multicellular organisms. O₂ is actually a toxic mutagenic gas that is highly oxidizing and combustible. It is thought that plants are largely to blame for polluting the earth′s atmosphere with O₂ owing to the development of photosynthesis by blue-green algae over 2 billion years ago. The rise of the plants and atmospheric O₂ levels placed evolutionary stress on organisms to adapt or become extinct. This implies that all the surviving creatures on our planet are mutants that have adapted to the “abnormal biology” of O₂. Much of the adaptation to the presence of O₂ in biological systems comes from well-coordinated antioxidant and repair systems that focus on converting O₂ to its most reduced form, water (H₂O), and the repair and replacement of damaged cellular macromolecules. Biological systems have also harnessed O₂′s reactive properties for energy production, xenobiotic metabolism, and host defense and as a signaling messenger and redox modulator of a number of cell signaling pathways. Many of these systems involve electron transport systems and offer many different mechanisms by which antioxidant therapeutics can alternatively produce an antioxidant effect without directly scavenging oxygen-derived reactive species. It is likely that each agent will have a different set of mechanisms that may change depending on the model of oxidative stress, organ system, or disease state. An important point is that all biological processes of aerobes have coevolved with O₂ and this creates a Pandora′s box for trying to understand the mechanism(s) of action of antioxidants being developed as therapeutic agents.