Chemical, biological and medical controversies surrounding the Fenton reaction

A critical evaluation is made of the role of the Fenton reaction (Fe-2 + H2O2 --> Fe3+ + (OH)-O-. + OH-) in the promotion of oxidative damage in mammalian systems. Following a brief, historical overview of the Fenton reaction, including the formulation of the Haber-Weiss cycle as a mechanism for the catalysis of hydroxyl radical production, an appraisal is made of the biological relevance of the reaction today, following recognition of the important role played by nitric oxide and its congers in the promotion of biomolecular damage. In depth coverage is then given of the evidence (largely from EPR studies) for and against the hydroxyl radical as the active oxidant produced in the Fenton reaction and the role of metal chelating agents (including those of biological importance) and ascorbic acid in the modulation of its generation. This is followed by a description of the important developments that have occurred recently in the molecular and cellular biology of iron, including evidence for the presence of 'free' iron that is available in vivo for the Fenton reaction. Particular attention here is given to the role of the iron-regulatory proteins in the modulation of cellular iron status and how their functioning may become dysregulated during oxidative and nitrosative stress, as well as in hereditary haemochromatosis, a common disorder of iron metabolism. Finally, an assessment is made of the biological relevance of ascorbic acid in the promotion of hydroxyl radical generation by the Fenton reaction in health and disease.